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Inflammatory mediators Flashcards

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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
LTB4 (leukotriene)
Chemotactic and reduces pain thresholds
26
Peptido leukotrienes (LTC4, LTD4, LTE4)
Bronchoconstriction, increased vascular permeability, chemotaxis
27
Kinins
Redness, swelling, pain, airway constriction, hypotension. Strong vasodilator (with resulting hypotension)
28
Histamine occurrence
Endogenous amine. In nearly every tissue. Highest concentrations in lung, skin, stomach
29
Mast cell histamine
- Stored in mast cells and basophils - Slow turnover - Found preformed in granules - Histamine boundd by ionic bonds to heparin-protein complex within the granules
30
Non-mast cell histamine
- Uncertain function - Rapid turnover - In CNS cells - In epidermis and other rapidly growing tissues - Enterochromaffin-like cells in fundus of stomach release histamine
31
Synthesis of histamine
Histidine-->Histamine | Catalyzed by L-histidine decarboxylase
32
Histamine metabolism
Enzymes for metabolism widely distributed. Metabolites have little or no pharmacological activity.
33
Oral admin of histamine
Large doses without causing effects
34
Intracutaneous admin of histamine
Triple response: itching, pain, redness/wheal/flare
35
Flare
- diffuse redness around and beyond original redness - develops more slowly - nerves dilating neighboring arterioles
36
Edema or wheal formation
Occurs in 1-2 min in same area as original redness. | Increased capillary permeability w/leakage of post-capillary venules
37
Intranasal histamine
Intense itching Sneezing (reflex) Hypersecretion (reflex) Nasal blockage (vasodilation and edema) with increased secretions
38
IV histamine
- 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
Endogenous histamine release
Antigen interaction with IgE Ab on mast cells and basophils leading to clinical effects.
40
Non-cytolytic histamine release
- Mainly basic substances - Kinins - C3a/C5a (anapylatoxins) - Protamine (heparin antagonist) - Dextrans and plasma substitutes - Morphine - Curare alkaloids
41
Cytolytic histamine release
- Mechanical or thermal insult | - Some venoms
42
Clinical uses of histamine
- Limited. | - By inhalation can assess bronchial reactivity. May be used intradermally to assess sensory neuron integrity
43
Types of histamine receptors
H1, H2, H3, H4
44
H1 receptors cause what to occur?
- Bronchoconstriction - Contraction of GI smooth muscle - Increased capillary permeability - Pruritis (itch) and pain - Release of catecholamines from adrenal medulla
45
H2 receptors cause what to occur?
-Gastric acid secretion -Inhibition of T lymphocyte mediated toxicity Suppression of Th2 cells and cytokines
46
H3 and H4 receptors cause what to occur?
Present on histaminergic nerve terminals and many immune cells
47
Mixed H1 and H2 receptor mediated responses
- 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
Triple response caused by histamine
Vasodilation (H1 and H2) Flare (H1 and probably H2) Wheal (increased capillary permeability primarily H1) Pain and itching (primarily H1)
49
Prostanoids synthesis
- By Phospholipase A2 (release arachidonic acid from membrane phospholipids). - Availability of arachidonic acid is the control step in prodction of PGs and thromboxane
50
What are prostagladins and thromboxanes derivatives from?
Prostanoic acid (20 carbon fatty acid with a cyclopentane ring)
51
PG2 precursor
Arachidonic aicd
52
PG1 precursor
8,11,14 eicosatrienoic acid
53
Are prostanoids stable molecules?
No. Short half lives and are intended to have local actions.
54
Cylclooxygenase (COX)
- Key enzyme in 2 step synthesis of PGH2 in the cell | - 2 isozymes exist (COX1 and COX2)
55
COX1
Found in platelets | Constitutively expressed in most cell and thought to protect gastric mucosa
56
COX2
- 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
Degradation of COX products
- Chemical hydrolysis or rapid enzymatic degradaion - Uptake into cells by transport protein with subsequent degradation - Short half-lives due to systemic effects
58
COX products
- Made by numerous cell types - Prostaglandins and thromboxane: synthesized on demand, liberated from cells, bind to cell membrane receptors to cause biological effects.
59
Platelets produce?
Thromboxane (vasoconstrictor)
60
Endothelium produces?
Prostacyclin (vasodilator)
61
Mast cells produce?
PGD2 (bronchoconstrictor)
62
Prostaglandin receptors?
``` DP (PGD) FP (PGF) IP (PGI2) TP (TXA2) EP (PGE)--4 subtypes EP1 through EP4 ```
63
Inflammatory effects of prostaglandins
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
Therapeutic relevance of COX products
Inflammation Fever CV disease (important in platelet aggregation)
65
What produces fever?
IL-1-->PGs-->Fever
66
What causes pain?
Cytokines, bradykinin, other mediators stimulate PGs and those stimulate pain
67
Leukotriene synthesis
- 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
5-lipoxygenase
Cytosolic enzyme that is translocated from cytosol to membranes by binding to protein 5-lipoxygenase activating protein (FLAP)
69
LTC4, LTD4, LTE4
Peptidoleukotrienes or cysteinyl leukotrienes | Slow reacting substance of anaphylaxis
70
Where are leukotrienes generated?
Predominantly in the leukocytes
71
What primarily makes LTB4
PMNs
72
What primarily makes peptido-leukotrienes
Mast cells and basophils
73
How can cells that lack 5-lipoxygenase make leukotrienes?
By transcellular metabolism
74
Transcellular metabolism
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
HETEs
Chemokinetic (random) and chemotactic (directed)--enhance directed and random migration of WBCs
76
LTB4
- LTB4 receptor - Chemotaxis of WBCs - Leukocyte adhesion, enzyme release and production or reactive oxygen species - Hyperalgesia or pain threshold reduction
77
LTC4, LTD4, LTE4 (Peptidoleukotrienes or cytsteinyl leukotrienes) recepors
``` Cys LTR1 (LTD4 receptor)--interacts preferentially with LTD4. Cys LTR2 (LTC4 receptor)--interacts with LTC4 and LTD4 ```
78
LTC4, LTD4, LTE4 (Peptidoleukotrienes or cytsteinyl leukotrienes) cause what when interacting with Cys LTR1?
- Bronchoconstriction - Eosinophil chemotaxis and chemokine secretion - Increased vascular permeability - Increased mucous production - DC maturation and migration - Smooth muscle proliferation
79
LTC4, LTD4, LTE4 (Peptidoleukotrienes or cytsteinyl leukotrienes) cause what when interacting with Cys LTR2?
- Endothelial and macrophage activation | - Fibrosis
80
Relevance of LTC4/LTD4
Imporntant in asthma
81
Relevance of LTB4
Not sure. May be responsible for attracting WBCs to release proteases and cause damage
82
Kinin synthesis
Extracellular in blood or interstitial fluid (not in cells)
83
What kinins are mediators with inflammatory activities?
Bradykinin and kallidin
84
Hfa
Activated Hageman factor, part of clotting cascade
85
Plasmin
Enzyme that digests fibrin
86
Kininase I
Carboxypeptidase N or anaphylatoxin inactivator removes carboxy terminal arginine and leads to kinin degradation
87
Kininase II
Angiotensin convertng enzyme (ACE) or dipeptide hydrolase that leads to degradation of kinins
88
Kinin receptors
B1 and B2
89
Kinin actions via B1 receptor
- 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
Kinin actions via B2 receptor
- 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
Inter-relationships of Kinin, complement, coagulation and fibrinolytic pathways
- Affecting one pathway may perturb another | - Specific therapeutic action in any one pathway is difficult

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