Lecture 6 - Inflammation Flashcards Preview

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

Flashcards in Lecture 6 - Inflammation Deck (61):
1

What are the aims of inflammation?

• dilute
• destroy
• isolate
• initiate repair

2

What are the two forms of inflammation?

Acute
Chronic

3

Which are the most important cells in inflammation?

• endothelial cells
• neutrophils

4

What are the most important mediators of inflammation?

Cytokines

5

What is the general function of the mediators?

To initiate the inflammatory response

6

Where do the chemical mediators of inflammation come from?

• cells
• plasma proteins

7

Describe amplification of mediators

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

8

Why do the chemical mediators have a short half life?

Don't want inflammation to continue on unregulated.
We want this to be a short response

9

Describe the sequence of events in acute inflammation

→ Injury
1. Vasodilation
2. Vascular leakage and oedema
3. PMN migration

10

What are some other names for neutrophils?

Polymorphs
PMNs

11

What is the benefit of oedema?

Dilute the toxins/pathogens

12

Describe the effects of vasodilation

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

13

What is transudate?

Protein-poor filtrate

14

What is the effect of increased interstitial osmotic pressure?

Increases oedema
(water wants to move out of the capillaries)

15

Describe Retraction

• Endothelial cells pull apart from each other
• Cytoskeletal reorganisation

Brought about by
• TNF
• IL-1

16

What brings about increased vascular permeability?

Histamines
( + Bradykinins, Leukotrienes)

17

How long does increased vascular permeability take?

15-30 mins

18

Which severe injuries can bring about endothelial damage?

Heat
UV injury
Bacterial toxins

19

What is transcytosis?

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

20

What causes transcytosis?

VEGF: vascular endothelial growth factor

21

Which things can induce damage of endothelial cells?

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

22

Why do macrophages release proteolytic enzymes?
What is the result?

In an attempt to destroy pathogens
However, the enzymes can also damage the endothelial cells

23

Describe neutrophil recruitment

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

3. Chemotaxis
• CXCL8

24

What is the effector function of neutrophils?

• Phagocytosis
• Degranulation
• Mopping up debris (phagocytosis)

25

What are in the neutrophil granules?

Anti-microbial compounds

• Proteolytic enzymes
• Defensins

26

Describe the sequence of events in acute inflammation

1. Oedema
2. Neutrophils
3. Monocytes / macrophages

27

Describe how neutrophils are 'selected out'

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

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

Histamine
Thrombin

29

What causes margination?

Crowding and engorged circulation

30

Where is ICAM-1?
What does it bind?

It's on the endothelium
It binds LFA on the neutrophil

31

Where is P-selectin?
What does it bind?

On the endothelium
It binds Sialyl-Lewis X

32

What is the receptor responsible for diapedesis?
Describe the receptor interaction

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

33

What is another name for diapedesis?

Transmigration

34

How do neutrophils know where to go after diapedesis?

Chemotaxis

35

What is a really important cytokine for chemotaxis?
Describe what happens

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

What are some generic chemo-attractants?

• Bacterial products (LPS)
• Complement
• Chemokines (IL-8)

37

What are the two derivations of chemical mediators of inflammation?

• Cell derived
• Plasma derived

38

Describe plasma derived mediators

Often enzymes that require activation

39

Which plasma proteins are important chemical mediators of inflammation?

Complement system
Kinin system
Clotting system
Fibrinolytic system

40

Which chemical mediator systems are important?

• Plasma proteins
• Arachidonic acid metabolites
• cytokines and chemokines
• vasoactive amines

41

What initiates the plasma chemical mediator system?

What initiates this?

Factor XII
• Hageman factor

Hageman factor triggered by Activated platelets

42

What does Factor XII trigger?

What is important about this?

Kinin cascade
Clotting cascade
Fibrinolytic system
Complement cascade

It is important to note that these systems are all interrelated

43

Which mediator is produced by the kinin cascade?
Discuss this

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

44

Which factor is produced by the clotting cascade?
What is its role in inflammation?

Thrombin

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

2. Expression of Selectins on endothelium for leukocyte recruitment

45

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

What is their effect?

"Anaphalotoxins"

• C3a
• C5a

Recruitment of white blood cells

46

What is the most important vasoactive amine?

Histamine

47

Describe the action of Histamine

Which cells release it?

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

Derived from:
• Mast cells
• Basophils

48

Describe the action of Nitric oxide (NO)

• Bronchodilation
• Vasodilation

• Regulation of thrombus

49

What are some arachidonic acid metabolites?
What is their function?

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

50

Which drugs target the arachidonic acid pathway?

NSAIDS
• They target COX (important in this pathway)

Steroid
• Targets Phospholipases
• More potent anti-inflammatory effect

51

What type of mediator are leukotrienes?

Arachidonic acid metabolite

52

What are eicosanoids?

aka Arachidonic acid metabolites

53

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

Inhibit arachidonic acid metabolite production through targeting of Phospholipases

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

54

Where do NSAIDS affect the Arachidonic acid pathway?

COX
This is further down the pathway
Thus is less potent

55

Which is the major inhibitory interleukin?

IL-10

56

How can we inhibit acute inflammation through cytokines?

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

57

What are some systemic effects of acute inflammation?

• fever
• leukocytosis

58

What is leukocytosis?

Elevated white blood cell count

59

Which mediators suppress inflammation?

(Endogenous) Glucocorticoids
IL-10

60

What is PAF?

Platelet activating factor

61

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

Prostacyclin
• Vasodilation

Thromboxane
• Vasoconstriction