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IHO 5 > Inflammatory mediators > Flashcards

Inflammatory mediators Flashcards

1
Q

What is inflammation?

A

Process that starts with sublethal tissue injury (mechanical, heat, chemicals, bacteria, viruses, Antigen-antibody reactions) and ends with permanent destruction of tissue or complete healing.

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2
Q

Mediators of inflammatory response

A
  • Endogenous subtnaces
  • stored or rapidly synthesized
  • only act at site of injury
  • redundancy (many substances or mediators can cause inflammatory symptoms)
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3
Q

Autacoids

A

Substances normally present in the body or formed there.

  • Brief lifetime
  • Act near site of synthesis
  • Sometimes called local hormoens (but they aren’t NTs or hormones)
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4
Q

What occurs during acute inflammation?

A
  • Changes in blood vessel caliber and flow
  • Increased vascular permeability (postcapilary venules leak large molecules, contraction of endothelium with spaces in between)
  • Leukocyte infiltration
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5
Q

What occurs with changes in blood vessel caliber and flow?

A

Increased flood, arteriolar dilation, slowing of flow, even stasis

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6
Q

What occurs with increased vascular permeability?

A

Postcapilary venules leak large molecules, contraction of endothelium with spaces in between

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7
Q

What occurs w/leukocyte infiltration?

A

Post-capillary venules, pavementing leukocytes, movement into extravascular space, chemotaxis.

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8
Q

What drugs target a single mediator?

A

Antihistamines and leukotriene modifiers

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9
Q

What drugs target multiple mediators?

A

NSAIDs, anti-inflammatory steroids

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10
Q

What drugs stop mediator production?

A

Synthesis inhibitors

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11
Q

What drugs stop mediator action?

A

Antagonists or inverse agonists

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12
Q

Major activities in inflammation

A 
Redness and heat--vasodilation
Swelling--increased vascular permeability
Pain
Chemotaxis
Airway constriction=broncoconstriction
Hypotension=decreased blood pressure
Fever
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13
Q

Redness mediators

A

Histamine
PGE2
PGI2
Kinins

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14
Q

Swelling mediators

A

Histamine
Peptido leukotrienes (LTC4, LTD4, LTE4)
Kinins

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15
Q

Pain mediators

A

PGE
PGI
LTB4
Kinins

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16
Q

Chemotactic mediators

A 
LTB3 (neutrophils etc.)
Peptido leukotrienes (eosinophils)
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17
Q

Fever mediators

A

PGEs

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18
Q

Airway constriction mediators

A

Histamine
Peptido leukotrienes
Kinins
PGD2

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19
Q

Hypotension mediators

A

Kinins

Histamine

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20
Q

Histamine

A

Redness, heat, swelling and airway constriction (no chemotaxis)

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21
Q

PGE2 and PGI2

A

Vasodilation, increased vascular permeability, pain

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22
Q

PGD2 and thromboxane

A

Bronchoconstriction

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23
Q

TXA2

A

Platelet aggregation and vasoconstriction

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24
Q

PGI2

A

opposes platelet aggregation and causes vasodilation

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25
Q

LTB4 (leukotriene)

A

Chemotactic and reduces pain thresholds

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26
Q

Peptido leukotrienes (LTC4, LTD4, LTE4)

A

Bronchoconstriction, increased vascular permeability, chemotaxis

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27
Q

Kinins

A

Redness, swelling, pain, airway constriction, hypotension. Strong vasodilator (with resulting hypotension)

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28
Q

Histamine occurrence

A

Endogenous amine.
In nearly every tissue.
Highest concentrations in lung, skin, stomach

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29
Q

Mast cell histamine

A
  • Stored in mast cells and basophils
  • Slow turnover
  • Found preformed in granules
  • Histamine boundd by ionic bonds to heparin-protein complex within the granules
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30
Q

Non-mast cell histamine

A
  • Uncertain function
  • Rapid turnover
  • In CNS cells
  • In epidermis and other rapidly growing tissues
  • Enterochromaffin-like cells in fundus of stomach release histamine
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31
Q

Synthesis of histamine

A

Histidine–>Histamine

Catalyzed by L-histidine decarboxylase

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32
Q

Histamine metabolism

A

Enzymes for metabolism widely distributed. Metabolites have little or no pharmacological activity.

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33
Q

Oral admin of histamine

A

Large doses without causing effects

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34
Q

Intracutaneous admin of histamine

A

Triple response: itching, pain, redness/wheal/flare

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35
Q

Flare

A
  • diffuse redness around and beyond original redness
  • develops more slowly
  • nerves dilating neighboring arterioles
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36
Q

Edema or wheal formation

A

Occurs in 1-2 min in same area as original redness.

Increased capillary permeability w/leakage of post-capillary venules

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37
Q

Intranasal histamine

A

Intense itching
Sneezing (reflex)
Hypersecretion (reflex)
Nasal blockage (vasodilation and edema) with increased secretions

38
Q

IV histamine

A
  • BP decreases (vasodilation, increased capillary permeability, fluid loss). May have secondary increase
  • Tachycardia
  • Bronchoconstriction
  • Flushing of face
  • Headache
  • Wheal and flare
  • Stimulates mucus secretion
  • Stimulation of gastric acid secretion
39
Q

Endogenous histamine release

A

Antigen interaction with IgE Ab on mast cells and basophils leading to clinical effects.

40
Q

Non-cytolytic histamine release

A
  • Mainly basic substances
  • Kinins
  • C3a/C5a (anapylatoxins)
  • Protamine (heparin antagonist)
  • Dextrans and plasma substitutes
  • Morphine
  • Curare alkaloids
41
Q

Cytolytic histamine release

A
  • Mechanical or thermal insult

- Some venoms

42
Q

Clinical uses of histamine

A
  • Limited.

- By inhalation can assess bronchial reactivity. May be used intradermally to assess sensory neuron integrity

43
Q

Types of histamine receptors

A

H1, H2, H3, H4

44
Q

H1 receptors cause what to occur?

A
  • Bronchoconstriction
  • Contraction of GI smooth muscle
  • Increased capillary permeability
  • Pruritis (itch) and pain
  • Release of catecholamines from adrenal medulla
45
Q

H2 receptors cause what to occur?

A

-Gastric acid secretion
-Inhibition of T lymphocyte mediated toxicity
Suppression of Th2 cells and cytokines

46
Q

H3 and H4 receptors cause what to occur?

A

Present on histaminergic nerve terminals and many immune cells

47
Q

Mixed H1 and H2 receptor mediated responses

A
  • Cardiac effects (increased HR, increased force of contraction, increased arrhythmias, slows AV conduction)
  • Vasodilato effects (H1 rapid dilator, short lived; H2 slower dilation, more sustained)
48
Q

Triple response caused by histamine

A

Vasodilation (H1 and H2)
Flare (H1 and probably H2)
Wheal (increased capillary permeability primarily H1)
Pain and itching (primarily H1)

49
Q

Prostanoids synthesis

A
  • By Phospholipase A2 (release arachidonic acid from membrane phospholipids).
  • Availability of arachidonic acid is the control step in prodction of PGs and thromboxane
50
Q

What are prostagladins and thromboxanes derivatives from?

A

Prostanoic acid (20 carbon fatty acid with a cyclopentane ring)

51
Q

PG2 precursor

A

Arachidonic aicd

52
Q

PG1 precursor

A

8,11,14 eicosatrienoic acid

53
Q

Are prostanoids stable molecules?

A

No. Short half lives and are intended to have local actions.

54
Q

Cylclooxygenase (COX)

A
  • Key enzyme in 2 step synthesis of PGH2 in the cell

- 2 isozymes exist (COX1 and COX2)

55
Q

COX1

A

Found in platelets

Constitutively expressed in most cell and thought to protect gastric mucosa

56
Q

COX2

A
  • Not found in platelets
  • Expressed constitutively in brain and kidney
  • Can be induced by certain serum factors, cytokines, growth factors in other tissues and at inflammation sites
  • More important isozyme for production of prostaglandins and thromboxane in inflammation
57
Q

Degradation of COX products

A
  • Chemical hydrolysis or rapid enzymatic degradaion
  • Uptake into cells by transport protein with subsequent degradation
  • Short half-lives due to systemic effects
58
Q

COX products

A
  • Made by numerous cell types
  • Prostaglandins and thromboxane: synthesized on demand, liberated from cells, bind to cell membrane receptors to cause biological effects.
59
Q

Platelets produce?

A

Thromboxane (vasoconstrictor)

60
Q

Endothelium produces?

A

Prostacyclin (vasodilator)

61
Q

Mast cells produce?

A

PGD2 (bronchoconstrictor)

62
Q

Prostaglandin receptors?

A 
DP (PGD)
FP (PGF)
IP (PGI2)
TP (TXA2)
EP (PGE)--4 subtypes EP1 through EP4
63
Q

Inflammatory effects of prostaglandins

A

Fever (PGE’s most potent)
Vasodilation (PGEs and PGI2)
Increased vascular permeability (PGEs and PGI2)
Pain (PGEs cause pain, PGEs and PGI2 lower pain threshold)

64
Q

Therapeutic relevance of COX products

A

Inflammation
Fever
CV disease (important in platelet aggregation)

65
Q

What produces fever?

A

IL-1–>PGs–>Fever

66
Q

What causes pain?

A

Cytokines, bradykinin, other mediators stimulate PGs and those stimulate pain

67
Q

Leukotriene synthesis

A
  • limitation: availability of arachionic acid
  • Active molecules: HETEs, LTB4, LTC4, LTD4
  • Arachidonic acid–>5-HPETE–>Leukotriene A4 and then to Leukotriene B4 or Leukotriene C4 (Leukotriene C4 can then go on to D4 and D4 can progress to E4).
68
Q

5-lipoxygenase

A

Cytosolic enzyme that is translocated from cytosol to membranes by binding to protein 5-lipoxygenase activating protein (FLAP)

69
Q

LTC4, LTD4, LTE4

A

Peptidoleukotrienes or cysteinyl leukotrienes

Slow reacting substance of anaphylaxis

70
Q

Where are leukotrienes generated?

A

Predominantly in the leukocytes

71
Q

What primarily makes LTB4

A

PMNs

72
Q

What primarily makes peptido-leukotrienes

A

Mast cells and basophils

73
Q

How can cells that lack 5-lipoxygenase make leukotrienes?

A

By transcellular metabolism

74
Q

Transcellular metabolism

A

LTA4 travels to other cell types and is converted to LTC4 or LTB4.
Mixture of cells at inflammatory site can influence the exact leukotrienes that are ultimately produced.

75
Q

HETEs

A

Chemokinetic (random) and chemotactic (directed)–enhance directed and random migration of WBCs

76
Q

LTB4

A
  • LTB4 receptor
  • Chemotaxis of WBCs
  • Leukocyte adhesion, enzyme release and production or reactive oxygen species
  • Hyperalgesia or pain threshold reduction
77
Q

LTC4, LTD4, LTE4 (Peptidoleukotrienes or cytsteinyl leukotrienes) recepors

A 
Cys LTR1 (LTD4 receptor)--interacts preferentially with LTD4.
Cys LTR2 (LTC4 receptor)--interacts with LTC4 and LTD4
78
Q

LTC4, LTD4, LTE4 (Peptidoleukotrienes or cytsteinyl leukotrienes) cause what when interacting with Cys LTR1?

A
  • Bronchoconstriction
  • Eosinophil chemotaxis and chemokine secretion
  • Increased vascular permeability
  • Increased mucous production
  • DC maturation and migration
  • Smooth muscle proliferation
79
Q

LTC4, LTD4, LTE4 (Peptidoleukotrienes or cytsteinyl leukotrienes) cause what when interacting with Cys LTR2?

A
  • Endothelial and macrophage activation

- Fibrosis

80
Q

Relevance of LTC4/LTD4

A

Imporntant in asthma

81
Q

Relevance of LTB4

A

Not sure. May be responsible for attracting WBCs to release proteases and cause damage

82
Q

Kinin synthesis

A

Extracellular in blood or interstitial fluid (not in cells)

83
Q

What kinins are mediators with inflammatory activities?

A

Bradykinin and kallidin

84
Q

Hfa

A

Activated Hageman factor, part of clotting cascade

85
Q

Plasmin

A

Enzyme that digests fibrin

86
Q

Kininase I

A

Carboxypeptidase N or anaphylatoxin inactivator removes carboxy terminal arginine and leads to kinin degradation

87
Q

Kininase II

A

Angiotensin convertng enzyme (ACE) or dipeptide hydrolase that leads to degradation of kinins

88
Q

Kinin receptors

A

B1 and B2

89
Q

Kinin actions via B1 receptor

A
  • Bradykinin and kallidin w/o terminal arg more active
  • Chronic inflammatory effects
  • Induced after trauma
  • May be involved with cytokine production and more long-term effects
  • Hypotension and pain
90
Q

Kinin actions via B2 receptor

A
  • Kallidin and Bradykinin more active
  • Hypotension (potent vasodilators)
  • Increased capillary permeability and edema formation
  • Algesic agents–cause pain and stimulate nerve endings
  • Contract gut smooth muscle slowly
  • Contract airway smooth muscle
  • Release catecholamines from adrenal medlla
  • Release prostaglandins
91
Q

Inter-relationships of Kinin, complement, coagulation and fibrinolytic pathways

A
  • Affecting one pathway may perturb another

- Specific therapeutic action in any one pathway is difficult

IHO 5 (5 decks)

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