acute inflammation Flashcards
define acute inflammation
Series of protective changes occurring in living tissue as a response to injury, can’t happen after death
it is a dynamic homeostatic mechanism limited to higher organisms
list the 5 cardinal signs of inflammation
- Rubor - redness
- Calor - heat
- Tumor - swelling
- Dolor - pain
- Loss of function
what are the 6 causes of acute inflammation (the aetiology)
microorganisms mechanical trauma chemical physcical dead tissue hypersensitivity
microorganisms as a cause of acute inflammation
viruses, bacteria, fungi, parasites (pathogenic organisms cause infection)
mechanical trauma as a cause of acute inflammation
injury to tissue (all injuries even sterile i.e. surgery)
chemical causes of acute inflammation
upset stable environment, acid/alkali (upset pH), bile (alkali) and urine (acidic) (irritation when in inappropriate place e.g. peritoneum)
physical causes of acute inflammation
extreme conditions e.g. heat (sunburn), cold (frostbite), ionising radiation (e.g. gamma ray source)
dead tissue as a cause of acute inflammation
cell necrosis irritates adjacent tissue, acute inflammation at the boundary between the dead and living tissue
hypersensitivity as a cause of acute inflammation
several classes of reaction, responses to antigens and antibodies e.g. allergies
what is the process of acute inflammation
- Series of microscopic events - we see the consequences of these effects
- Localised to affected tissue - generally not about the whole body
Take place in the microcirculation = capillary beds, fed by arterioles and drained by venules
- Localised to affected tissue - generally not about the whole body
what are the steps in acute inflammation (pathogenesis)
- Changes in vessel radius - flow
- Change in the permeability of the vessel wall - exudation i.e. what flows in/out of the vessel
Movement of neutrophils (acute inflammatory cells) from the vessel to the extravascular space
- Change in the permeability of the vessel wall - exudation i.e. what flows in/out of the vessel
local changes in vessel radius and blood flow
- Transient arteriolar constriction - few moments, probably protective
- Local arteriolar dilation - active hyperaemia
- Relaxation of vessel smooth muscle - ANS or mediator derived
Called the triple response - flush, flare, wheal
how does increased radius affect flow
- Increased arteriolar radius causes increased local tissue blood flow
- Results in observed redness and heat (blood is closer to the surface)
a tiny amount of change in the radius produces a huge change in the amount of substance moving through a vessel
- Results in observed redness and heat (blood is closer to the surface)
increased permeability in blood vessels
- Localised vascular response (happens in a specific vessel at a specific time)
- Microvascular bed (doesn’t happen all over)
- Endothelial leak - fluid and protein not held in vessel lumen (imbalance of Starling forces)
Locally produced chemical mediators
what are the effects of increased permeability
○ Net movement of plasma from capillaries to extravascular space
Process is exudation, what is leaked is exudate - fluid rich in protein (plasma) includes immunoglobulin and fibrinogen
○ Fluid loss –> increased velocity (h)
○ Rate of flow slows - stasis (slowing of the flow)
Stasis produces a change in flow characteristics in vessel because blood is a non-Newtonian fluid
what are the effects of exudation
○ Oedema formed - accumulation of fluid in the extravascular space
○ Explains swelling of tissue in acute inflammation
Swelling causes pain –> reduced function
describe normal laminar flow
working from the edge of the blood vessel towards the centre: plasma, erythrocytes, WBC
what determines laminar flow
Laminar flow is due to the size of the particles floating within the blood. Biggest particles flow through the middle
flow through vessels in inflammation
- Neutrophil polymorphonuclear leukocyte is most important cell
- Neutrophil; polymorph; NPL
- Loss of normal laminar flow
- Red cells aggregate in the centre of the lumen
Neutrophils found near endothelium
phases of emigration of neutrophils
- Margination - neutrophils move to endothelial aspect of lumen
- Pavementing - neutrophils adhere to endothelium with adhesion molecules
- Emigration - neutrophils squeeze between endothelial cells (active process) to extravascular tissues
Note diapedesis - happens to red cells, passive movement of cells from the vessel lumen into the extravascular space
examples of acute inflammation
- Gingivitis - inflammation of the gums, occurs commonly in leukaemia
- Pleural inflammation - inflammation on the surface of the lung
- Appendicitis
- Acute pyelonephritis - kidney, inflammation in the tubules
Bacterial endocarditis - inflammation of the heart valves, leads to vegetations, occurs most commonly as a result of septicaemia, seen in drug users who are sharing needles
outline resolution of acute inflammation
- Inciting agent isolated and destroyed
- Macrophages move in from blood and phagocytose debris then leave
- Epithelial surfaces regenerate
- Inflammatory exudate filters away
- Vascular changes return to normal
Inflammation resolves
what are the benefits of acute inflammation
- Rapid response to non-specific insult
- Cardinal signs and loss of function - transient protection of inflamed area
- Neutrophils destroy organisms and denature antigen for macrophages
- Plasma proteins localise process
Resolution and return to normal
what are the outcomes of acute inflammation
- Resolution
- Suppuration - pus formation
- Organisation - beginning of healing
- dissemination
Chronic inflammation - long term result of healing and repair
how is inflammation at anatomical locations named?
stucture - itis e.g. peritoneal cavity - peritonitis meninges - meningitis EXCEPTIONS: lungs - pneumonia pleural cavity - pleurisy
what is the role of neutrophils in acute inflammation
- Mobile phagocytes
○ Recognise foreign antigen
○ Move towards it - chemotaxis (detect chemical and move towards it, moving up the concentration gradient)
○ Adhere to organism- Granules possess oxidants (e.g. hydrogen peroxide) and enzymes (e.g. proteases)
- Release granule contents
- Phagocytose and destroy foreign antigen
what are the consequences of neutrophil action
○ Neutrophils die when granule contents released
○ Produce a ‘soup’ of fluid, bits of cell, organisms, endogenous proteins - pus (marker of inflammatory processes)
○ Might extend into other tissues, progressing the inflammation
what is the role of plasma proteins in acute inflammation
- Fibrinogen - coagulation factor, forms fibrin (polymer) and clots exudate, localises inflammatory process
Immunoglobulins in plasma specific for antigen - humoral immune response (see immunology lectures)
what are the 4 mediators of acute inflammation
- Molecules on endothelial cell surface membrane
- Molecules released from cells
- Molecules in the plasma
Molecules inside cells
what are the collective effects of mediators
- Vasodilatation
- Increased permeability
- Neutrophil adhesion (Pavementing)
- Chemotaxis
Itch and pain
what molecules are released from cells in acute inflammation
histamine, serotonin, prostaglandins, cytokines and chemokines, NO, oxygen free radicals
what is the role of histamine
○ Preformed in granules in mast cells beside vessels, platelets, basophils
○ Released as a result of local injury; IgE mediated reactions
○ Causes vasodilatation, increased permeability
Acts via H1 receptors on endothelial cells
what is the role of 5-hydroxytryptamine
○ Preformed in platelets in granules
○ Released when platelets degranulate in coagulation
○ Vasoconstriction - reduce radius of the vessel, reduces the flow, makes the vessel easier to block if it is leaking
Also acts as a neurotransmitter
what are the role of prostaglandins
arachidonic acid metabolites which run through the cyclo-oxygenase pathway
○ Many cells (endothelium and leukocytes)
○ Many promote histamine effects and inhibit inflammatory cells
○ Thromboxane A2 promotes platelet aggregation and vasoconstriction - the opposite effect to PGD2, PGE2, etc
○ Latter: effectiveness of non-steroidal anti-inflammatory drugs
what are the roles of cytokines and chemokines
○ Small molecules produced by macrophages, lymphocytes, endothelium in response to inflammatory stimuli
○ Pro-inflammatory and anti-inflammatory effects
§ Different molecules have different effects, dynamic balance between the 2 effects
Stimulate intracellular pathways and signalling
what is the role of nitric oxide
○ Various cells
○ Smooth muscle relaxation, anti-platelet, regulate leukocyte recruitment to inflammatory focus
what are the roles of oxygen free radicals
H2O2, OH-, O2-
○ Destroy molecules in order to gain electrons, help with the breakdown process
○ Released by neutrophils on phagocytosis
○ Amplify other mediator effects
signalling molecules inside cells
- Pattern associated molecular patterns:
○ Microbial antigen
○ Genetically hard wired to recognise antigens as foreign
○ Innate and adaptive immunity (non-specific)- Danger associated molecular patterns
○ Substances released in response to stimulus - Stimulate pattern recognition receptors on cell membranes
- Activate inflammatory response
- Danger associated molecular patterns
intracellular inflammatory pathways
- NF-kB (nuclear factor kappa-B) pathway
- MAPK (mitogen-activated protein kinase)
○ Stimulated in inflammation via surface receptors e.g. toll-like receptors (TLRs)
○ Regulates pro-inflammatory cytokine production and inflammatory cell recruitment - JAK-STAT (Janus kinase - signal transducer and activator to transcription) pathway
Direct translation of extracellular signal to molecular expression
- MAPK (mitogen-activated protein kinase)
interaction of 4 enzyme cascades in plasma
- Blood coagulation pathways
- Fibrinolysis
- Kinin system
- Complement cascade
blood coagulation pathways
○ Clots fibrinogen in exudate
Interacts widely with other systems
fibrinolysis
○ Breaks down fibrin, helps maintain blood supply
Fibrin breakdown products vasoactive
kinin system
Bradykinin: pain
complement cascade
○ Ties inflammation with immune system
Active components stimulate increased permeability, chemotaxis, phagocytosis, cell breakdown
what are the general effects of mediators
- Vasodilation and constriction
- Altered permeability
- Neutrophil adhesion
- Chemotaxis
- Itch and pain
- Mediators have +ve and -ve effects
- Result is a dynamic balance
- Favours and inhibits acute inflammation (not usually at the same time)
- Relative to need (inflammatory response is proportional to the injury caused)
what are the immediate systemic effects of acute inflammation
- Pyrexia - raised temperature
○ Endogenous pyrogens from white cells act centrally- Feel unwell
○ Malaise, anorexia, nausea
○ Abdominal pain and vomiting in children - Neutrophilia - raised white cell count
○ Bone marrow releases/produces
- Feel unwell
what are the long term systemic effects of inflammation
- Lymphadenopathy: regional lymph node enlargement (immune response - switch over from innate to adaptive immunity)
- Weigh loss - catabolic process of making neutrophils, proteins etc
Anaemia
- Weigh loss - catabolic process of making neutrophils, proteins etc
suppuration
- Pus formation: dead tissue, organisms, exudate, neutrophils, fibrin, red cells, debris
Pyogenic membrane surrounds pus: capillary sprouts grow into the piece of fibrin, neutrophils, fibroblasts. Walls off pus
what is an abscess
- Collection of pus (suppuration) under pressure
- Single locule or multiloculated
- Points and discharges
- Collapses - healing and repair
describing pus in other places
- Empyema - in a hollow viscus
○ Gall bladder, pleural cavity
Pyaemia - discharge to bloodstream
organisation
- Granulation tissue characteristic
- Healing and repair
Leads to fibrosis and formation of a scar
- Healing and repair
what is granulation tissue
universal patch, repair kit for all damage
Formed of: new capillaries (angiogenesis), fibroblasts and collagen, macrophages
dissemination
- Spread to bloodstream - patient ‘septic’
- Bacteraemia - bacteria in blood
- Septicaemia - growth of bacteria in blood
Toxaemia - toxic products in blood
what are the effects of systemic infection
- Shock - inability to perfuse tissues
- Clinical picture of early septic shock
○ Peripheral vasodilation –> tachycardia –> hypotension
○ Often pyrexia
Sometimes haemorrhagic skin rash
- Clinical picture of early septic shock
pathogenesis of septic shock
- Systemic release of chemical mediators from cells into plasma
- increased HR compensates (for loss of SVR and tachycardia to maintain CO)
- Bacterial endotoxin released - leads to pyrexia
- Activation of coagulation (resulting in disseminated intravascular coagulation, vasodilatation and haemorrhagic skin rash)
- WHEN COMPENSATION FAILS:
○ Raised HR insufficient to maintain CO, SVR low so BP falls
○ Reduced perfusion of tissues: tissue hypoxia, loss of cell tissue and organ function
outcome of septic shock
- Rapidly fatal
- Tissue hypoxia –> cell death (affects kidneys, brain, heart)
- Haemorrhage
- Requires urgent intervention and support
○ Awareness and early recognition
○ Ability of young people to compensate - get very ill very quickly
○ Admit to hospital and intensive care
