(PM3A) Inflammation Flashcards
What is inflammation?
Response to stimuli that can cause body damage
What is the function of inflammation?
Protection from danger/ damage
Promote healing
CAN lead to tissue damage
What are the cardinal signs for inflammation?
(1) Heat – calor
(2) Redness – rubor
(3) Swelling – tumor
(4) Pain –dolor
(5) Loss of function
What is the timescale of an inflammatory response?
(1) Irritant/ vaccine injection/ injury
- Production of inflammatory mediators
- Elimination of pathogen
(2) Resolution
- Removal of inflammatory stimuli
(3) Post-resolution
- Influx of adaptive immune cells
What is the innate immune response?
Largely inflammation
Non-adaptive
How is the innate immune response triggered?
Pattern recognition receptors
What is the adaptive immune response?
Triggered or recruited by innate immune response
Immunological memory
What is the summary of inflammatory events of a physical injury, e.g. a splinter?
(1) Pathogens recognised by macrophages
(2) Stimulates sentinel cells (mast cells)
(3) Signals to blood vessels to recruit other components
- Leukocytes
- Increase blood vessel dilatation
(4) Movement of fluid into affected area from blood vessel
(5) Phagocytosis of pathogen
What is pattern recognition?
The trigger of inflammatory responses
Pattern recognition receptors (PRRs) triggered by pattern-associated molecular patterns (PAMPs)
What are some examples of pattern recognition receptors?
Toll-like receptors
How can different stimuli cause a different inflammatory response?
Different pattern recognition receptors
What are sentinel cells?
Mast cells/ dendritic cells/ macrophages
Release cytokines + inflammatory mediators
Trigger inflammatory responses
What are mast cells?
Reside in most tissues
Activated by IgE + C3a + C5a proteins
Release pro-inflammatory mediators
- e.g. histamine/ prostaglandins/ platelet activating factor
What is the role of endothelial cells in the inflammatory response?
(1) Respond to pro-inflammatory mediators
(2) Release mediators that cause vasodilatation
- e.g. prostaglandins + nitric oxide
(3) Express adhesion molecules for leukocytes
- e.g. selectins
What are some inflammatory-mediating cells that reside in the tissue?
(1) Mast cells
(2) Endothelial cells (of blood vessels)
(3) Macrophages
(4) Leukocytes
(5) Platelets
What are the vascular events of the inflammatory response?
Account for rubor/ tumor/ calor
Triggered by cytokines + mediators
Causes:
(1) Vasodilatation
(2) Vascular permeability to fluid
(3) Expression of adhesion molecules on endothelial cells
What are proteolytic cascades?
Convert factor XIIa from plasma into pro-inflammatory products
These products activate the complement cascade
ø C1-C9
What are leukocytes?
Form the pus
Roll + extrude endothelial cell layer to enter inflammation site
Attracted to pathogens by chemotaxis
Engulf + kill + digest pathogens
What is leukocyte extrusion?
(1) Rolling of leukocytes down endothelial cells of blood vessel (veins ONLY) by inflammatory site
(2) Binding to selectins on endothelial membrane
(3) Extrusion of leukocytes through endothelial cells into tissue
What are some later cellular events in inflammation?
Caused by monocytes + macrophages
Secondary arrival hours after neutrophils
What is chemotaxis?
Movement of leukocytes to site of pathogen
Following chemical signals
Process in inflammatory response
How does failure of healing affect inflammation?
Causes chronic inflammation
Leads to loss of function
Can be:
(1) Hypersensitivity – e.g. asthma
(2) Infectious disease – e.g. tuberculosis
(3) Auto-immune diseases
What are some molecular hallmarks of non-resolving inflammation?
(1) TNF increasing
(2) IFNs increasing
(3) IL-6 increasing
What are some examples of acute inflammatory responses?
(1) Hayfever
(2) Contact dermatitis
(3) Acute asthma attack
(4) Uritcaria
What are some examples of chronic inflammatory responses?
(1) Asthma
(2) Rheumatoid arthritis
(3) Atherosclerosis
What is the role of chemokines and cytokines?
Mediation of inflammatory signals
What are cytokines?
Protein/ peptide signalling molecules
Modulate function of other cells in inflammation + immunity
C3a/ TNF-alpha/ IL-1 are some major pro-inflammatory cytokines
What are chemokines?
Type of cytokine
Control leukocyte migration
e.g. C3a/ C5a/ LTB4
What happens following intradermal injection of inflammation?
(1) Flush - arterial vasodilatation
(2) Oedema/ swelling (wheal)
(3) Flare –sensory nerve induced dilatation
What occurs following stimulation of H1 receptors by histamine?
(1) GIT constriction
(2) Bronchial smooth muscle constriction
(3) Dilatation of blood vessels – stimulates endothelial cells
(4) Itch – associated with wound healing
How is histamine released?
Mast cell degranulation
Caused by C3a, C5a + IgE
What are eicosanoids?
Lipid-derived mediators
What is the major component for forming lipid-derived inflammatory mediators?
Arachidonic acid
What are prostanoids?
Type of eicosanoids
Formed by the action of cyclooxygenases (COXs)
Most are termed ‘prostaglandins’
How many types of prostanoid receptor are there?
5 classes
DP/ FP/ IP/ EP/ TP
EP have 4 subtypes
What is the key prostanoid that influences the inflammatory response?
Prostaglandin E2 – PGE2
PGI2 also important
How many PGE2 cause fever?
Can alter thermoregulation of hypothalamus
What are some types of eicosanoids?
(1) Prostanoids/ prostaglandins
(2) Leukotrienes
(3) Lipoxins
What is 5-lipoxygenase?
Leukotrienes
What is the role of leukotrienes?
Constrict bronchial smooth muscle
Increase vascular permeability
Evoke wheal + flare
Antagonists of leukotriene receptors used in treated of asthma
- e.g. montelukast
What properties do lipoxins have?
Pro resolving properties
Help to resolve inflammation
What is platelet activating factor (PAF)?
Stimulates the signs + symptoms of inflammation
Induces pain
Formation is inhibited by glucocorticoids
What is the significance of nitric oxide as an inflammatory mediator?
Bioactive gas
Evokes vasodilatation
High concentrations are cytotoxic + can kill pathogens
What is TNF-alpha?
Type of inflammatory mediator
What is the significance of bradykinin as an inflammatory mediator?
Peptide mediator that can modulate inflammatory response
What is the use of histamine antagonists?
Treatment of hypersensitivity reactions
Oral/ topical creams
Why is histamine antagonist use limited?
A lot of redundancy
Lots of other pro-inflammatory pathways
When are histamine antagonists often used?
(1) Hayfever
(2) Urticaria
(3) Can be used as anti-emetics
What is loratadine indicated for?
Symptomatic relief of allergy
Such as hayfever or chronic idiopathic urticaria
What is the mechanism of action of aspirin?
Non-selective inhibition of COX1 + COX 2
COX1 irreversibly inhibited
What is the mechanism of action of naproxen?
Non-selective inhibition of COX1 + COX2
What is the mechanism of action of ibuprofen?
Non-selective inhibition of COX1 + COX2
What is the mechanism of action of diclofenac?
Non-selective inhibition of COX1 + COX2
Which type of COX has ‘housekeeping’ properties?
GIT/ renal/ platelets
COX1
What is the purpose of NSAID treatment for inflammation?
Reduce the formation of
(1) Prostaglandins
(2) Thromoxane
Which enzyme(s) do most NSAIDs inhibit?
COX1 and COX2
What does the suffice -coxib mean?
COX2 selective inhibitors
What are some examples of COX2 selective inhibitors?
(1) Celecoxib
(2) Etoricoxib
What is ‘COX’?
Cyclooxygenase enzymes
What is a risk of COX2 selective inhibitors?
Cardiovascular events
How do NSAIDs exhibit an antipyretic effect?
Prostaglandin-2 formation in hypothalamus is triggered by fever causing pathogens
– e.g. bacterial endotoxin/ IL-1
(1) NSAIDs prevent prostaglandin production so reduce fever
Do NOT affect normal maintenance body temperature
What is the role of prostaglandins in pain?
Sensitise nociceptors (pain receptors)
How do NSAIDs reduce inflammation?
(1) Reduce inflammation caused by prostaglandins
(2) Reduces vasodilatation caused by prostaglandin-2
(3) Reduce oedema by reducing vascular permeability
ONLY reduce inflammatory response dependent on prostaglandin formation
What are some unwanted side effects of NSAIDs?
(1) Gastric COX1 produces prostaglandins which decrease acid secretion + promote mucosa formation
– Can cause mild/ severe symptoms
– Mild: Discomfort, dyspepsia, diarrhoea
– Severe: Bleeding, ulceration
(2) Skin reactions
(3) Pregnancy
– especially in 1st and 2nd trimesters
– ibuprofen may be used in 3rd trimester
(4) Renal effects
– caused by reduction in renal blood flow
– Contraindicated in patients with renal failure
– Analgesic nephropathy associated with overuse/ abuse of OTC NSAIDs
What is a benefit of COX2 selective inhibitors, regarding the GIT?
Fewer GI side effects
What are some cardiovascular complications of NSAIDs?
Mainly related to thrombotic events
Why may COX2 selective inhibitors cause more cardiovascular side effects?
Reduced PGI2 production
Why did diclofenac become a POM from P med?
Increases thrombotic event risk
Why is paracetamol not considered an NSAID?
Has no effect on COX1 and COX2
No anti-inflammatory effect
DESPITE a strong analgesic and antipyretic effect
What is a glucocorticoid?
Corticosteroid
Which hormones control the production of corticosteroids within the body?
(1) Corticotrophin-releasing hormone (CRH)
2) Adrenocorticotrophin hormone (ACTH
What factors up-regulate corticosteroid production?
(1) Stress
(2) Pro-inflammatory mediators
What type of feedback does cortisol (hydrocortisone) provide for itself?
Negative feedback loop
Inhibits its own release
Where is cortisol produced?
In the adrenal glands
Where is corticotrophin-releasing hormone (CRH) produced?
In the hypothalamus
Where is adrenocorticotrophin (ACTH) produced?
In the pituitary gland
What is the mechanism of action of glucocorticoids (corticosteroids)?
(1) Pass from blood vessel via lipid biller into target cell
(2) Binds to cytosolic glucocorticoid receptor
(3) Once bound it translocates into the nucleus
(4) Binds to response elements on the chromosome
(5) Alters genetic transcription
What effect does low circulating concentrations of glucocorticoid have on the normal inflammatory response?
Reduces response
How do glucocorticoids reduce the inflammatory response?
(1) Reduce synthesis of inflammatory mediators
(2) Affect function of inflammatory cells
(3) Reduce cardinal signs of inflammation
(4) Provides immunosuppressant actions
(5) Reduce almost all stimuli + actions of the inflammatory response
Name two examples of molecules inhibited by glucocorticoids.
(1) Phospholipase A
(2) COX2
What are the anti-inflammatory properties of glucocorticoids?
(1) Reduce prostaglandin synthesis
(2) Reduce cytokine generation
(3) Reduce complement proteins in blood plasma
(4) Reduce production of nitric oxide
(5) Increase anti-inflammatory factors
–IL-1
– IL-10
–Annexin-1
What effect do glucocorticoids have on anti-inflammatory cells?
(1) Decreased movement of neutrophils
(2) Decreased action of leukocytes/ immune cells
(3) Decreased fibroblast function
What are some common uses of glucocorticoids?
(1) Asthma
(2) Topically in inflammatory conditions of the skin
(3) Hypersensitivity reactions
(4) Auto-immune + inflammatory disorders
– Arthritis
– IBS
What are some unwanted effects of glucocorticoids?
Can be severe
(1) Reduced wound healing
(2) Susceptibility to injury/ infection
(3) Changes in electrolytes – e.g. hypoglycaemia
(4) Osteoporosis
(5) Mental health problems
(6) Cushing’s syndrome
– can be caused by prolonged exposure to corticosteroids
Why does glucocorticoid use have to be tapered down gradually?
Glucocorticoid use impairs natural glucocorticoid production in the body
Could produce a dramatic increase in inflammatory response following cessation of treatment
