Inflammation Flashcards
What are the clinical signs of inflammation?
erythema
oedema
heat
pain
What is inflammation?
The body’s response to tissue injury
What causes inflammation?
chemical agents
cold, heat
trauma
invasion of microbes
Why have inflammation?
serves to destroy, dilute or wall off the injurious agent and induce repair
BUT can be potentially harmful in uncontrolled
What is barrier immunity?
What are active barrier defences?
physical barrier of protection e.g. skin, lungs, gut
active barrier defence e.g. cilia, secretions, anti-bacterial peptides
Describe the innate immune defence
Provides a rapid local response to pathogens
Ready to activate at any time
No memory
No specificity
Preprogrammed, generic response
Recognition by pattern recognition receptors
Which cells of the immune system recognise the threat?
Professional Antigen Presenting Cells (APC’s)
- mast cells
- dendritic cells
- macrophages / monocytes
Which cells of the immune system contain and destroy a threat?
Phagocytes - neutrophils - macrophages Granulocytes - neutrophils - eosinophils - mast cells / basophils
What are the main three proteins of the innate immune system? Give the function of each
Acute phase proteins - e.g CRP - opsonise or present pathogens Cytokines - chemical signals which modulate cell activity or attract cells (chemokines) Complement - multiple funcitons - opsonisation, killing, activation chemo-attraction
Give an overview of the three stages of the acute phase response
Recognise problem - danger signal - recognised by innate immune cells Response - cellular activation/recruitment - cytokine/complement activation Deal with problem - phagocytosis/destruction of pathogen - resolution of inflammation or recruitment of adaptive immune response
Describe the proteins involved in recognising a threat
Pathogens are recognised by Pattern Recognition Receptors (PRR’s)
These are on every innate immune cell
PRR’s recognise pattern-associated molecular patterns (PAMPs) that occur on microbes
- but not in humans so distinguish self from non-self
Which cells are responsible to initiating the acute phase?
mast cells
- detect injury
- release histamine and other mediators
- initiating inflammatory response
What are the effects of histamine?
vasodilation
endothelial junction widening (increased permeability)
irruption of nerve endings (itch)
What are the other important mediators of inflammation?
Arachidonic acid metabolites (eicosanoids)
- prostaglandins and thromboxanes
- COX pathway
- cause vasodilation and probing oedema
- but also protective (gastric mucosa)
- COX blocked by aspirin and NSAIDs
Leukotrienes
- lipoxygenase pathway
- are chemotaxis and vasoconstrictors
- cause increased vascular permeability and bronchospasm
- leukotriene receptor antagonists (e.g. monteleukast) used in asthma
In what situations/conditions can it be useful to block inflammatory mediators? x3
Histamine
- useful in allergy to block histamine induced vasodilation
Arachidonic acid metabolites
- block progtaglandins and COX pathway with NSAIDs and aspirin to reduce pain and fever
- prostaglandins - used in pulmonary hypertension
Leukotrienes
- used in asthma to reverse leukotriene induced bronchospasm
The physiology of the acute phase:
What are the 4 things that cause the symptoms in the acute phase?
Vasodilation
Increased vascular permeability
Cytokines
Mediators
–> erythema, oedema, heat, pain
What are the 3 mechanisms of inflammation?
Vasodilation - increased blood flow and pooling creating redness and warmth
Increased permeability - plasma proteins and cells extravasate creating swelling. Fluid loss into tissue leads to concentration of red blood cells and slowed blood flow (stasis) in vessels
Movement of white cells - blood stasis and activation signals leads to immune cells migrating towards offending agent
What is feeling systematically unwell when you can a chest infection an example of?
local inflammation can cause systemic inflammation
this is particularly medicated by acute phase cytokines
What the main important acute phase cytokines? x3
IL-1
TNF-alpha
IL-6
Where are these 3 acute phase cytokines produced?
macrophages
Where do these 3 acute phase cytokines act?
Endothelium Hypothalamus Fat, muscle Liver Bone Marrow Dendritic cells
What is the effect of acute phase cytokines on the endothelium?
vasodilation
increased permeability
activates cells
What is the effect of acute phase cytokines on the hypothalamus?
Increased body temp
–> Decreased bacterial/viral replication
Increased antigen processing
What is the effect of acute phase cytokines on fat/muscle?
proteins/energy mobilisation allow increase temp
decreased bacterial/viral replication
Increased antigen processing
What is the effect of acute phase cytokines on the liver?
actue phase protein production
complement activation
facilitate phagocytosis
What is the effect of acute phase cytokines on the bone marrow?
neutrophil mobilisation
phagocytosis
What is the effect of acute phase cytokines on the dendritic cells?
TNF stimulates migration of lymph nodes and maturation
initiation of adaptive response
Give examples of when drugs are used to block the acute phase
We use anti cytokine therapies to block the acute phase response
Acute TNF-alpha
- NICE approve for inflammatory bowel disease and rheumatoid arthritis
Anti IL-1 and IL-6
- rheumatoid arthritis
Overproduction of TNF-alpha and IL-1 can cause…….. ……….
How?
septic shock
- endotoxin (LPS) from gram-negative bacteria
- blood circulation
- massive macrophage activation in liver and spleen
- overproduction of TNF-alpha and IL-1
- dilation of blood vessels and massive leakage of fluid into tissues
- widespread blood clotting (disseminated intravascular coagulation)
- multiple organ failure
What are the 5 possible outcomes of acute inflammation?
- complete restitution
- healing with scar formation
- abscess formation (encapsulation and pus)
- granuloma formation
- chronic inflammation
Chronic inflammation occurs when the acute phase cannot be resolved. Give 3 examples
- persistent injury or infection e..g ulcer, TB
- prolonged toxic agent exposure (silica)
- autoimmune diseaes states (SLE, RA)
What are the 3 mechanisms of chronic inflammation?
cellular infiltration (granulomas) tissue destruction by inflammatory cells (COPD) attempts at repair with firbros and angiogenesis (new vessel formation)
How is acute inflammation terminated? x3
- eradication of offending grant should lead to discotinuation of the inflammatory response
- most mediators are very short lived and are degraded immediately (neutrophils have only a short life span)
- anti-inflammatory cytokines (TGF-beta, and IL-10) can inhibit production of pro-inflammatory cytokines
What biomarkers can be used to detect and monitor the acute phase?
Biomarkers that increase or decrease in response to to injury, infection or inflammation Acute phase proteins - CRP, C3/C4, fibrinogen, ferritin Negative control proteins - A1antitrypsin - albumin - transferrin
What is CRP?
What does it do?
What does it respond to?
- C-reactive protein
- Pathogen recognition molecule, binds to bacteria and fungal cell wall phospholipids
- opsonises pathogen and activates classical complement cascade by binding C1q
- goes up within 24-48 hours in response to: injury, inflammation and infection
What is ESR?
What can it indicate and why?
Erythrocyte sedimentation rate = rate at which erythrocytes settle out of unclothed blood in one hour
Normally, erythrocytes are very bouyant and settle slowly
Erythrocytes are negatively charged and repel each other (no aggregation occurs)
In presence of acute phase reactants, erythrocytes aggregate due to loss of negative charge resulting in increased sedimentation.
Can indicate presence of acute phase proteins
What is leukocytosis?
Leukocyte release results from a direct effect of IL-1 and IL-6 on bone marrow neutrophil stores
Exaggeration of this can result in a ‘Leukaemoid reaction’ or left shift with release of immature precursors
What are the characteristic cell types in acute and chronic inflammation?
Acute
- first neutrophils
- then monocytes to clear away dead neutrophils
Chronic
- lymphocytes, macrophages and plasma cells
