What is acute inflammation?
Acute inflammation is a dynamic homeostatic response which maintains the integrity of the organism. It involves a series of protective mechanisms that occur in response to injury.
What are the 5 cardinal signs of inflammation?
- Rubor- redness
- Calor- heat
- Tumour- swelling
- Dolor- pain
- Loss of function
What can the cardinal signs of inflammation be explained by?
The sequence of pathological events taking place.
What are the aetiologies of inflammation?
Infection (bacteria/viruses/parasites/fungi etc)
Trauma (even sterile surgery)
Dead tissue (cell necrosis irritates adjacent tissue)
Hypersensitivity
Where does acute inflammation take place?
Microcirculation
What is the microcirculation?
- Capillary beds, fed by arterioles and drained by venules
- Extracellular space and fluid around it
- Lymphatic channels and drainage
- Starling forces control the fluid flux across the membrane
- Dynamic balance (hydrostatic/colloid osmotic pressures, compartments and physical constants
What is the pathogenesis of acute inflammation? (Steps)
Changes in the arterial radius (FLOW)
Changes in the permeability of the vessel wall (EXUDATION)
Movement of neutrophils from the vessel to the extravascular space
What are the local changes in vessel radius and blood flow?
- Transient arteriolar constriction (few movements, probably protective)
- Local arteriolar dilation (active hyperaemia)
- Relaxation of vessel smooth muscle (autonomic NS/mediator derived)
What is the triple response?
Flush, flare, wheal.
What does an increased arteriolar radius cause?
Increased blood flow to the local tissue- results in the cardinal redness and heat.
What does increased permeability involve?
There is an endothelial leak-fluid and protein is not held in the vessel lumen due to an imbalance of Starling forces. It also involves locally produced chemical mediators.
What are the effects of increasing permeability?
There is a net movement of plasma from the capillaries to the extravascular space. This process is called exudation- the fluid leaked is called the exudate.
What is an exudate rich in?
Immunoglobulin and fibrinogen.
What are the effects of exudation?
Oedema- accumulation of fluid in the extravascular space
Explains swelling as a cardinal sign of inflammation- this can lead to a localised loss of function in the affected area. Oedema.
Where are plasma, WBC and erythrocytes situated within the vessel during normal laminar flow?
Plasma all around, WBC in middle, erythrocytes surrounding them.
Where are plasma, WBC and erythrocytes situated within the vessel during inflammation?
Plasma remains, WBC extend to the surface, erythrocytes (RBC) move into the middle.
What are the phases of neutrophil emigration?
When neutrophils migrate from pre-endothelium in the vessel to the extravascular space.
What are the phases of neutrophil emigration?
- Margination- neutrophils move to the endothelial aspect of the lumen
- Pavementing- neutrophils adhere to the endothelium
- Emigration- neutrophils squeeze between endothelial cells (active process) to the extravascular tissues
What are the outcomes of acute inflammation?
Resolution
Suppuration (pus formation)
Organisation
Chronic inflammation
What is the ideal outcome of acute inflammation?
- Inciting agent is isolated and destroyed (pathogenic destruction)
- Macrophages move in from the 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 a non-specific insult
- Cardinal signs and loss of function provide transient protection of the inflamed area
- Neutrophils destroy organism and denature the antigen for macrophages
- Plasma proteins localise the process
- Can be resolved and restored to normal
What is inflammation characterised by in terms of nomenclature?
-‘itis’ prefix
What is inflammation called in the lungs?
Pneumonia
What is inflammation called in the pleural cavity?
Pleurisy
What do neutrophils do?
Neutrophils are mobile phagocytes- they recognise foreign antigens and move towards them in the chemotaxis process. They then adhere to them. Granules produce oxidants and enzymes which phagocytose and destroy the foreign antigen.
What are the consequences of neutrophil action?
- Neutrophils die when the granule is released
- Produces a soup of fluid/bits of cell organisms/ endogenous proteins = PUS
- Might extend into other tissues, progressing the inflammation
What plasma proteins play a role within acute inflammation?
Fibrinogen
Immunoglobulin
What does fibrinogen do?
Fibrinogen- coagulation factor (forms fibrin, clots the exudate which localises the inflammatory process)
What does immunoglobulin do?
Immunoglobulin- specific for antigen (humoral immune response).
What are the mediators of acute inflammation?
- Molecules on endothelial cell surface membrane
- Molecules released from the cells
- Molecules in plasma
- Molecules in the cells
How do molecules on the endothelial cell surface membrane mediate acute inflammation?
- Sticky- adhesion molecules appear on endothelial cells to make neutrophils stick
- P-selectin interacts with the neutrophil surface
What molecules are released from cells to mediate the inflammatory response?
Histamine Seratonin Prostaglandins Cytokines Nitric oxide Oxygen free radicals
How does histamine work?
Histamine is preformed in most cells beside vessels/platelets/basophils. It is released as a result of local injury, is IgE mediated, and causes vasodilation and an increased permeability.
How does serotonin work?
Preformed in platelets, released when platelets deregulate in coagulation, vasoconstriction.
How do prostaglandins work?
These include many cells, many promote histamine effects and inhibit inflammatory cells, thromboxane A2 promotes platelet aggregation and vasodilation, latter effectiveness of NSAIDs.
How do cytokines work?
These are small molecules produced by macrophages and lymphocytes in response to inflammatory stimuli, have pro-inflammatory and anti-inflammatory effects, can stimulate intracellular pathways and signalling.
How does nitric oxide work?
Nitric oxide is released from various cells, has a key role in relaxation of smooth muscle, anti-platelet, and regulation of leukocyte recruitment to inflammatory focus.
How do oxygen free radicals work?
Released by neutrophils on phagocytosis, amplify other mediator effects.
How do molecules inside the cells mediate an inflammatory response?
- Pattern associated molecular patterns- microbial antigen, genetically hard-wired to recognise, innate and adaptive immunity
- Danger associated molecular patterns- substances released in response to a stimulus
- Stimulate pattern recognition receptors on the cell membrane
- Activate inflammatory response
What are the 4 enzyme cascade interactions?
- Blood Coagulation Pathway-clots fibrinogen in exudate, interacts widely with other systems.
- Fibrinolysis- breaks down protein/fibrin
- Kinin System (Bradykinin=pain)
- Complement Cascade-ties inflammation with the immune system
What are the overall effects of inflammatory mediators?
- Vasodilation / vasoconstriction
- Altered permeability
- Neutrophil adhesion
- Chemotaxis
- Itch and pain
- Positive and negative effects
- Dynamic balance
- Favours and inhibits acute inflammation
- Relative to need
What are the immediate systemic effects of inflammation?
Pyrexia- raised temperature (endogenous pyrogens from white cells act centrally).
Malaise- feeling unwell (malaise/anorexia/nausea), abdominal pain and vomiting in children
Neutrophilia- raised count of white blood cells (shows immune response of bone marrow release)
What are the long-term systemic effects of inflammation?
Lymphadenopathy- regional lymph node enlargement (immune response)
Weight loss- catabolic process
Anaemia
What is the process of pus formation called?
Suppuration
What does pus contain?
Dead tissue, organisms, exudate, neutrophils, fibrin, red blood cells, debris.
What is the membrane surrounding pus called?
Pyogenic membrane
What is an abscess?
An abscess is pus under pressure.
Are abscesses always at a single location?
No- they can be singular or multi-located.
What does collapse of an abscess lead to?
Healing and repair.
What is pus called in a hollow cavity?
Empyema.
What is pus discharge to the bloodstream called?
Pyaemia.
What is organisation a characteristic of?
Granulation tissue.
What does organisation involve?
Involves healing and repair, leading to fibrosis and the formation of a new scar.
What is granulation tissue?
Universal patch repair kit for all injuries.
What is the granulation tissue composed of?
New capillaries (angiogenesis)
Fibroblasts/collagen
Macrophages
What is dissemination?
Pathogenic spread into the bloodstream.
What is a patient subject to dissemination referred to as?
Septic.
What is bacteraemia?
Presence of bacteria in the blood.
What is septicaemia?
Growth of bacteria in the blood.
What is toxaemia?
Presence of toxic products in the blood.
What are the systemic effects of septic infection?
Shock- inability to perfuse tissues.
Peripheral vasodilation, tachycardia, hypotension, pyrexia, haemorrhagic skin rash.
What is the pathogenesis of septic infection?
Bacterial endotoxin causes systemic release of chemical mediators- cause vascular response but heart has to compensate for this.
What is the outcome of septic shock?
Often fatal- especially in elderly who are less able to compensate
Major cell death (tissue hypoxia)
Haemorrhage
Needs rapid clinical intervention
In summary, what are the outcomes of acute inflammation?
Resolution Suppuration Organisation Dissemination Chronic inflammation
