Lecture 6 - Inflammation Flashcards
What are the aims of inflammation?
- dilute
- destroy
- isolate
- initiate repair
What are the two forms of inflammation?
Acute
Chronic
Which are the most important cells in inflammation?
- endothelial cells
* neutrophils
What are the most important mediators of inflammation?
Cytokines
What is the general function of the mediators?
To initiate the inflammatory response
Where do the chemical mediators of inflammation come from?
- cells
* plasma proteins
Describe amplification of mediators
One mediator is activated
This mediator then goes on to activate many more
(a cascade)
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
Describe the sequence of events in acute inflammation
→ Injury
- Vasodilation
- Vascular leakage and oedema
- PMN migration
What are some other names for neutrophils?
Polymorphs
PMNs
What is the benefit of oedema?
Dilute the toxins/pathogens
Describe the effects of vasodilation
• PMNs are able to migrate out
• Fluid leakage; transudate initially
→ later exudate
• Increased interstitial osmotic pressure
What is transudate?
Protein-poor filtrate
What is the effect of increased interstitial osmotic pressure?
Increases oedema
water wants to move out of the capillaries
Describe Retraction
- Endothelial cells pull apart from each other
- Cytoskeletal reorganisation
Brought about by
• TNF
• IL-1
What brings about increased vascular permeability?
Histamines
+ Bradykinins, Leukotrienes
How long does increased vascular permeability take?
15-30 mins
Which severe injuries can bring about endothelial damage?
Heat
UV injury
Bacterial toxins
What is transcytosis?
No change in junctions of endothelial cells
Membrane permeability increases
Flow of fluids through the cells using vesicles
What causes transcytosis?
VEGF: vascular endothelial growth factor
Which things can induce damage of endothelial cells?
Toxins
Bacteria
Immune cells
• e.g. Macrophages producing free radicals and proteolytic enzymes
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
Describe neutrophil recruitment
- Margination & rolling
• E and P selectin mediated
• Transient interactions - Adhesion
• Integrin mediated
• ICAM-1 and VCAM-1 on endothelial cells
• LFA-1 and VLA-4 on neutrophils - Diapedesis
• PECAM-1 homotypic interactions - Chemotaxis
• CXCL8
What is the effector function of neutrophils?
- Phagocytosis
- Degranulation
- Mopping up debris (phagocytosis)
What are in the neutrophil granules?
Anti-microbial compounds
- Proteolytic enzymes
- Defensins
Describe the sequence of events in acute inflammation
- Oedema
- Neutrophils
- Monocytes / macrophages
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
Which chemical mediator up-regulates selectin expression on endothelial cells?
Histamine
Thrombin
What causes margination?
Crowding and engorged circulation
Where is ICAM-1?
What does it bind?
It’s on the endothelium
It binds LFA on the neutrophil
Where is P-selectin?
What does it bind?
On the endothelium
It binds Sialyl-Lewis X
What is the receptor responsible for diapedesis?
Describe the receptor interaction
PECAM-1
Found on both neutrophil and endothelium
Self-interaction
What is another name for diapedesis?
Transmigration
How do neutrophils know where to go after diapedesis?
Chemotaxis
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
What are some generic chemo-attractants?
- Bacterial products (LPS)
- Complement
- Chemokines (IL-8)
What are the two derivations of chemical mediators of inflammation?
- Cell derived
* Plasma derived
Describe plasma derived mediators
Often enzymes that require activation
Which plasma proteins are important chemical mediators of inflammation?
Complement system
Kinin system
Clotting system
Fibrinolytic system
Which chemical mediator systems are important?
- Plasma proteins
- Arachidonic acid metabolites
- cytokines and chemokines
- vasoactive amines
What initiates the plasma chemical mediator system?
What initiates this?
Factor XII
• Hageman factor
Hageman factor triggered by Activated platelets
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
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
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
- Expression of Selectins on endothelium for leukocyte recruitment
Which complement derivatives have a direct impact on the inflammatory response?
What is their effect?
“Anaphalotoxins”
- C3a
- C5a
Recruitment of white blood cells
What is the most important vasoactive amine?
Histamine
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
Describe the action of Nitric oxide (NO)
- Bronchodilation
- Vasodilation
• Regulation of thrombus
What are some arachidonic acid metabolites?
What is their function?
1. Prostacyclin • vasodilation 2. Thromboxane • vasoconstriction 3. Leukotrienes 4. PAF
Which drugs target the arachidonic acid pathway?
NSAIDS
• They target COX (important in this pathway)
Steroid
• Targets Phospholipases
• More potent anti-inflammatory effect
What type of mediator are leukotrienes?
Arachidonic acid metabolite
What are eicosanoids?
aka Arachidonic acid metabolites
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)
Where do NSAIDS affect the Arachidonic acid pathway?
COX
This is further down the pathway
Thus is less potent
Which is the major inhibitory interleukin?
IL-10
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
What are some systemic effects of acute inflammation?
- fever
* leukocytosis
What is leukocytosis?
Elevated white blood cell count
Which mediators suppress inflammation?
(Endogenous) Glucocorticoids
IL-10
What is PAF?
Platelet activating factor
Describe the vasodilation / constriction interaction between two of the AA metabolites
Prostacyclin
• Vasodilation
Thromboxane
• Vasoconstriction
