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PATH30001 - Mechanisms of Disease > Lecture 6 - Inflammation > Flashcards

Lecture 6 - Inflammation Flashcards

1
Q

What are the aims of inflammation?

A
  • dilute
  • destroy
  • isolate
  • initiate repair
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2
Q

What are the two forms of inflammation?

A

Acute

Chronic

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3
Q

Which are the most important cells in inflammation?

A
  • endothelial cells

* neutrophils

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4
Q

What are the most important mediators of inflammation?

A

Cytokines

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5
Q

What is the general function of the mediators?

A

To initiate the inflammatory response

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6
Q

Where do the chemical mediators of inflammation come from?

A
  • cells

* plasma proteins

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7
Q

Describe amplification of mediators

A

One mediator is activated
This mediator then goes on to activate many more
(a cascade)

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8
Q

Why do the chemical mediators have a short half life?

A

Don’t want inflammation to continue on unregulated.

We want this to be a short response

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9
Q

Describe the sequence of events in acute inflammation

A

→ Injury

  1. Vasodilation
  2. Vascular leakage and oedema
  3. PMN migration
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10
Q

What are some other names for neutrophils?

A

Polymorphs

PMNs

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11
Q

What is the benefit of oedema?

A

Dilute the toxins/pathogens

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12
Q

Describe the effects of vasodilation

A

• PMNs are able to migrate out
• Fluid leakage; transudate initially
→ later exudate
• Increased interstitial osmotic pressure

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13
Q

What is transudate?

A

Protein-poor filtrate

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14
Q

What is the effect of increased interstitial osmotic pressure?

A

Increases oedema

water wants to move out of the capillaries

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15
Q

Describe Retraction

A
  • Endothelial cells pull apart from each other
  • Cytoskeletal reorganisation

Brought about by
• TNF
• IL-1

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16
Q

What brings about increased vascular permeability?

A

Histamines

+ Bradykinins, Leukotrienes

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17
Q

How long does increased vascular permeability take?

A

15-30 mins

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18
Q

Which severe injuries can bring about endothelial damage?

A

Heat
UV injury
Bacterial toxins

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19
Q

What is transcytosis?

A

No change in junctions of endothelial cells
Membrane permeability increases
Flow of fluids through the cells using vesicles

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20
Q

What causes transcytosis?

A

VEGF: vascular endothelial growth factor

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21
Q

Which things can induce damage of endothelial cells?

A

Toxins
Bacteria
Immune cells
• e.g. Macrophages producing free radicals and proteolytic enzymes

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22
Q

Why do macrophages release proteolytic enzymes?

What is the result?

A

In an attempt to destroy pathogens

However, the enzymes can also damage the endothelial cells

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23
Q

Describe neutrophil recruitment

A
  1. Margination & rolling
    • E and P selectin mediated
    • Transient interactions
  2. Adhesion
    • Integrin mediated
    • ICAM-1 and VCAM-1 on endothelial cells
    • LFA-1 and VLA-4 on neutrophils
  3. Diapedesis
    • PECAM-1 homotypic interactions
  4. Chemotaxis
    • CXCL8
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24
Q

What is the effector function of neutrophils?

A
  • Phagocytosis
  • Degranulation
  • Mopping up debris (phagocytosis)
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25
Q

What are in the neutrophil granules?

A

Anti-microbial compounds

  • Proteolytic enzymes
  • Defensins
26
Q

Describe the sequence of events in acute inflammation

A
  1. Oedema
  2. Neutrophils
  3. Monocytes / macrophages
27
Q

Describe how neutrophils are ‘selected out’

A

Rolling:
In the area of inflammation the endothelial cells start expressing Selectin molecules on their surface
These molecules bind transiently to Sialyl-Lewis X on the neutrophil

28
Q

Which chemical mediator up-regulates selectin expression on endothelial cells?

A

Histamine

Thrombin

29
Q

What causes margination?

A

Crowding and engorged circulation

30
Q

Where is ICAM-1?

What does it bind?

A

It’s on the endothelium

It binds LFA on the neutrophil

31
Q

Where is P-selectin?

What does it bind?

A

On the endothelium

It binds Sialyl-Lewis X

32
Q

What is the receptor responsible for diapedesis?

Describe the receptor interaction

A

PECAM-1
Found on both neutrophil and endothelium
Self-interaction

33
Q

What is another name for diapedesis?

A

Transmigration

34
Q

How do neutrophils know where to go after diapedesis?

A

Chemotaxis

35
Q

What is a really important cytokine for chemotaxis?

Describe what happens

A

IL-8
This is a cytokine subfamily

  • IL-8 released by inflammatory cells
  • IL-8R on neutrophils engaged
  • Polarisation of the neutrophil
  • Cytoskeletal rearrangements in neutrophils and migration towards the source of inflammation
36
Q

What are some generic chemo-attractants?

A
  • Bacterial products (LPS)
  • Complement
  • Chemokines (IL-8)
37
Q

What are the two derivations of chemical mediators of inflammation?

A
  • Cell derived

* Plasma derived

38
Q

Describe plasma derived mediators

A

Often enzymes that require activation

39
Q

Which plasma proteins are important chemical mediators of inflammation?

A

Complement system
Kinin system
Clotting system
Fibrinolytic system

40
Q

Which chemical mediator systems are important?

A
  • Plasma proteins
  • Arachidonic acid metabolites
  • cytokines and chemokines
  • vasoactive amines
41
Q

What initiates the plasma chemical mediator system?

What initiates this?

A

Factor XII
• Hageman factor

Hageman factor triggered by Activated platelets

42
Q

What does Factor XII trigger?

What is important about this?

A

Kinin cascade
Clotting cascade
Fibrinolytic system
Complement cascade

It is important to note that these systems are all interrelated

43
Q

Which mediator is produced by the kinin cascade?

Discuss this

A 
Bradykinin
 • Increases vascular permeability and arteriolar dilation
 • Causes pain
 • bronchial smooth muscle contraction
 • rapidly inactivated
44
Q

Which factor is produced by the clotting cascade?

What is its role in inflammation?

A

Thrombin

Role:
1. Fibrin clot formation
• Soluble fibrinogen → Insoluble fibrin clot

  1. Expression of Selectins on endothelium for leukocyte recruitment
45
Q

Which complement derivatives have a direct impact on the inflammatory response?

What is their effect?

A

“Anaphalotoxins”

  • C3a
  • C5a

Recruitment of white blood cells

46
Q

What is the most important vasoactive amine?

A

Histamine

47
Q

Describe the action of Histamine

Which cells release it?

A

Function:
• Endothelial cell contraction (increased vascular permeability)
• Increased expression of selections on endothelium

Derived from:
• Mast cells
• Basophils

48
Q

Describe the action of Nitric oxide (NO)

A
  • Bronchodilation
  • Vasodilation

• Regulation of thrombus

49
Q

What are some arachidonic acid metabolites?

What is their function?

A 
1. Prostacyclin
 • vasodilation
2. Thromboxane
 • vasoconstriction
3. Leukotrienes
4. PAF
50
Q

Which drugs target the arachidonic acid pathway?

A

NSAIDS
• They target COX (important in this pathway)

Steroid
• Targets Phospholipases
• More potent anti-inflammatory effect

51
Q

What type of mediator are leukotrienes?

A

Arachidonic acid metabolite

52
Q

What are eicosanoids?

A

aka Arachidonic acid metabolites

53
Q

What is the effect of glucocorticoids (steroids) on inflammation?

A

Inhibit arachidonic acid metabolite production through targeting of Phospholipases

Very potent response
(because it inhibits stuff early on in the pathway)

54
Q

Where do NSAIDS affect the Arachidonic acid pathway?

A

COX
This is further down the pathway
Thus is less potent

55
Q

Which is the major inhibitory interleukin?

A

IL-10

56
Q

How can we inhibit acute inflammation through cytokines?

A
  • more IL-10
  • reduce cells producing cytokines
  • reduce circulating cytokines with Mabs
  • receptor blockade with antagonists or mabs
57
Q

What are some systemic effects of acute inflammation?

A
  • fever

* leukocytosis

58
Q

What is leukocytosis?

A

Elevated white blood cell count

59
Q

Which mediators suppress inflammation?

A

(Endogenous) Glucocorticoids

IL-10

60
Q

What is PAF?

A

Platelet activating factor

61
Q

Describe the vasodilation / constriction interaction between two of the AA metabolites

A

Prostacyclin
• Vasodilation

Thromboxane
• Vasoconstriction

PATH30001 - Mechanisms of Disease (34 decks)

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