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Biochemistry 2 > Mediators of Inflammation > Flashcards

Mediators of Inflammation Flashcards

1
Q

What is COX?

A

cyclooxygenase enzyme

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2
Q

EPA

A

eicosapentaenoic acid

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3
Q

Eicosanoids

A

Family of lipid mediators derived from oxidative transformation of 20-carbon polyunsaturated fatty acids (e.g. 5,8,11,14-cis-eicosatetraenoic acid). Eicosanoids include prostaglandins, thromboxane and leukotrienes as the main family members. Eicosanoids are autacoid mediators.

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4
Q

Omega-6 (

A

20 carbon fatty acids with a terminal olefin bond 6 carbons ‘in’ from the terminal position (

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5
Q

Omega-3 (

A

20 carbon fatty acids with a terminal olefin bond at 3 carbons ‘in’ from the terminal position (

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6
Q

Why are eicosanoids called eicosanoids?

A

They derive from oxidative metabolism of PUFA, especially those with 20 carbons (Greek prefix eicosa-)

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7
Q

Biosynthesis of eicosanoids Prostaglandins and thromboxane

A

1 Cell membranes contain PUFA in their phospholipids. Arachidonic acid (AA) is the dominant PUFA in most cells 2 ‘Stimuli’ liberate AA – the substrate for COX 3 COX enzymes transform ‘free’ AA into prostaglandins (PGs) or thromboxane (Tx) 4 PGs exit cells, bind to receptors and transmit signal to cells

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8
Q

What is the arachidonic acid cascade?

A
  1. ) Phospholipase A2 cleaves off Arachadonic Acid from the PM
  2. ) COX Cyclooxygenase + O2 convert AA to Prostaglandin (PG)H2 endoperoxide
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9
Q

What is AA Cascade Table?

A

Image attached

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10
Q

Eicosanoid Biosynthesis: Key Points

A

• Cells’ capacity for eicosanoid biosynthesis is
latent. PGs or Tx are made, not stored, in cells.

• PG or Tx are made upon ‘demand’ – synthesis
occurs only when stimuli activate phospholipase
A2 to liberate AA from cellular phospholipids.

• PGs or Tx biosynthesis is limited in duration and
scope – by the availability of O2 and AA; by
auto-inactivation of COX enzyme; by rapid and
comprehensive metabolic degradation of PGs,
or spontaneous hydrolysis of Tx and PGI 2.

• Isomerase enzymes dictate which cells make
which PG or Tx. Most cells express COX.

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11
Q

Prostaglandins, thromboxane and
other eicosanoids are autacoid
mediators

A

• Stimuli activate eicosanoid synthesis.
• Eicosanoids mediate autocrine & paracrine
signaling nearby the cells that make them.
• Unlike hormones, autacoids are short-lived,
locally generated signaling mediators – rapid
metabolism via pulmonary 15-OH PGDH or
degradation limits their accumulation and
circulation via the blood stream

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12
Q

Prostaglandin & Thromboxane
Receptors Are Membrane Spanning
Proteins With 7 Domains

A

Image Attached

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13
Q
A
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14
Q

What prostaglandins does 15-OH PG dehydrogenase break down?

A

PGD2, PGE2, PGF2 (alpha)

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15
Q

What gets inactivated by Hydrolysis?

A

PGI2 (Prostacyclin) and TxA2 (Thromboxane)

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16
Q

What do PG isomerases do?

A

Convert PGH2 into
PGE2, PGF2(alpha), PGD2

17
Q

What do Tx synthase or
PGI synthase do?

A

Convert PGH2 into
TxA2 or PGI2

18
Q

What are Autacoids?

A

Autacoids or “autocoids” are biological factors which act like local hormones, have a brief duration, and act near the site of synthesis.

• Eicosanoids mediate autocrine & paracrine
signaling nearby the cells that make them.

• Unlike hormones, autacoids are short-lived,
locally generated signaling mediators – rapid
metabolism via pulmonary 15-OH PGDH or
degradation limits their accumulation and
circulation via the blood stream

19
Q

What do EP2, EP4 and I P receptors typically do in smooth muscle?

A

EP2, EP4 and I P receptors occupied by
their cognate ligands typically relax
smooth muscles (vasodilate blood
vessels).

  1. )PGE2 or PGI2 occupies EP4/IP receptor
  2. )Components assemble
  3. )cAMP increases
  4. )Smooth muscles relax
20
Q

What do FP and TP receptors typically do to smooth muscle?

A

FP and TP receptors occupied by their
cognate ligands contract smooth
muscles (vasoconstrict blood vessels).

1.) TxA2 occupies TP receptor

2.)Components assemble (PGF2alpha / FP Receptors, or TxA2/ TP
Receptors Coupled to Phospholipase C
and Gq)
3.)IP3 and Ca2+ increases

21
Q

How are COX-1 and COX-2 related?

A

They are isoenzymes of eachother.

COX-1 is constitutive while COX-2 is inducible.

22
Q

What does COX-1 do in the gut?

A

Physiological Stimulus, e.g. gastric acid

  • *PGE2 : EP receptors**
  • *Physiological Role:** Mucosal cytoprotection (i.e. prevents ulcers), gut motility

Deficit of PGE2 - Risk for ulcers

Excess of PGE2 - Diarrhea, cramps

23
Q

What does COX-1 do in reproductive organs?

A

Physiological Stimulus, e.g. endocrine hormones & mechanical ‘stretch’

PGE2: EP receptors

PGF2alpha: FP receptors

Physiological role: at term, dilate the cervix, contract the uterus -> parturition (delivery)

  • Deficit* of PGs - delayed birth
  • Excess* of PGs - Pre-mature labor, birth,
24
Q

What does COX-1 do in neonatal development?

A

Physiological Stimulus, e.g. fetal lung maturation

COX-1

PGE2 : EP receptors

Physiological role: maintain a patent ductus arteriosus in the fetus

At birth, maturation of neonatal lung ‘withdraws’ PGE2:ductus arteriosus closes

25
Q

Importance of COX-2 in the Kidney?

A

Cyclooxygenase-2 (COX- 2)
is normally expressed and has a
prominent physiological role in
the kidney

Physiological stimulus, e.g. renin,

COX-2 & COX-1

PGE2:EP receptors

Physiological role: renal blood flow, filtration & Na+ H2O excretion in the kidney

Deficit of PGs in kidney (especially in elderly) leads to Na+ and H2O retention (edema), mild hypertension (elevated blood pressure)

26
Q

How is Cyclooxygenase-2
(COX-2) induced during inflammation?

A
  1. ) Inflammation stimulates AA release
  2. ) COX-1 converts AA into PGE2
  3. ) PGE2 causes symptoms (Erythmia, Edema, Pain)
  4. ) Inflammation induces COX-2 expression
  5. ) COX-2 also converts AA into PGE2
  6. ) COX-2 derived PGE2 amplifies symptoms (Even worse Erythmia, Edema, Pain)
27
Q

What are Platelets and what do they do?

A

(Thrombocytes) Very small blood cells, that have
no nucleus. Platelets are specialized cells that aggregate
together & thereby physically obstruct a severed blood vessel.
Platelets serve as a scaffold for coagulation of blood (hemostasis).
Unwarranted platelet aggregation in coronary arteries is the cause
of heart attacks; in cerebral arteries it is the cause of strokes.
Platelets make an eicosanoid called thromboxane A2, _which
constricts blood vessels and amplifies platelet aggregation._

28
Q

What is the Endothelium?

A

(Endothelial cells) Cells that line the interior
of blood vessels. Endothelial cells are specialized cells that allow
blood to flow throughout the circulation without clotting.
Disruption of the endothelium lining simulates blood coagulation.
Endothelial cells make an eicosanoid called prostaglandin I 2
(Prostacyclin), _which relaxes blood vessels and inhibits platelet
aggregation. Endothelial cells and platelets balance
hemostasis/ thrombosis_

29
Q

I f most tissues express cyclooxygenase
(COX-1) how does the body modulate the
ratio of TxA2 and PGI 2?

A

COX-1 is widespread, BUT
isomerases & synthase enzyme vary
among different tissues/cells….so
different cells can make different
eicosanoids, and thereby exert
opposing physiological effects

30
Q

Partitioning of PGH2 for hemostasis

A

Image attached

31
Q

What are the steps from Thromboxane when injury occurs?

A
  1. )Collagen stimulates platelets
  2. ) Platelets make TxA2
  3. ) TxA2 aggregates platelets (TP receptors)
  4. ) TxA2 constricts vessel (TP receptors)

TxA2 formation
amplifies platelet
aggregation
via autocrine
& paracrine
signaling

32
Q

What stops thrombosis from
spreading throughout the
blood stream ? What keeps it local?

A

The stimulus (collagen) is
local…and another eicosanoid – PGI 2
(prostacyclin) – made by endothelial
cells opposes the actions of TxA2 on
blood vessels and platelets

• PLA2 activation -> AA
• AA + COX-1 -> PGH2
• PGH2 -> PGI 2 (prostacyclin)
• PGI 2 binds IP receptors on
platelets & smooth muscle
• PGI 2 inhibits platelet aggregation &
relaxes smooth muscle, therby dilating
blood vessels

33
Q

Do platelets have a nucleus?

A

Have NO nucleus
• They have NO capacity for de novo
transcription of proteins
• COX-2 cannot be induced in platelets

34
Q

How does heart attack happen?

A

I f endothelial cells’ COX-2 and COX-1 fails to
maintain adequate PGI 2 synthesis it may tip the
balance in favor of vessel occlusion if a plaque
ruptures ..this is what causes heart attacks

Adequate PGI 2
supports blood flow
past plaque.
Platelets Do
Not Aggregate

PGI 2 deficit allows
TxA2 to dominate.
Platelets aggregate.
Vessel is blocked

35
Q

What are the consequences
of eating a diet rich in
omega-3 fatty acids ?

A

EPA -> (by COX-1) PGH3 endoperoxide instead of PGH2.

PGH3 becomes TGI3 and TxA3 are made (by PG I & Tx Synthase)

TxA3 causes Weak Vasoconstriction
Inhibits platelet
aggregation
Weak platelet
aggregation

36
Q

Why are they called leukotrienes ?

A

Because they are made by
leukocytes and they all have a
conjugated triene in their structure

37
Q
A

Biochemistry 2 (8 decks)

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