Topic 2 - Accute Inflamation Flashcards
What is acute inflammation?
- Acute inflammation is the initial and often transient (only lasts a short time) series of tissue reactions to injury or irritation (noted histologically by the presence of neutrophils).
- Immflamuation is not a disease but instead a manifestation of disease
What are the benefits of inflammation?
- Destroys invading organisms
- “Walling off” (isolation) of an abscess cavity - prevents the spread of infection
What are the limitations of inflammation?
- Disease: eg an abscess in the brain will occupy limited space and compress the surrounding vital structures
- Fibrosis - Resulting from chronic inflammation - distorts tissue and can permanently alter their function.
What are the steps of acute inflammation?
1) Initial reaction of the tissue to injury
2) Vascular - Dilation of vessels due to smooth muscle relaxation in arteriolar walls
3) Exudation - Protein rich fluid leaks out of the vessels due to a high hydrostatic pressure within the vessel
4) Neutrophil polymorph recruitment
What are the outcomes of inflammation?
1) Resolution - Goes away
2) Suppurations - Pus formation eg an abscess
3) Organisation - Healing by fibrosis
4) Progression to chronic inflammation
What in organisation as an outcome of inflammation?
- Healing by fibrosis: occurs when there is substantial damage to connective tissue and the tissue lacks the ability to regenerate specialised cells
- Dead tissues are removed by macrophages
- The defect is then filled with granulation tissue
- The granulation tissue then gradually produces collagen to form a fibrous scar.
What are the causes of inflammation?
- Microbial infections: Bacteria, viruses
- Hypersensitivity reactions: Parasites
- Physical agents: Trauma, ionising radiation, heat and cold
- Chemicals: Corrosives, acids and alkalis
- Bacterial toxins: Toxins released by bacteria during infection
- Tissue necrosis: ischaemic infarction
What is a hypersensitivity reaction?
A reaction that occurs when the immune system causes an inappropriate or excessive immune response that damages tissue.
What is the normal appearance of acute inflammation?
- Redness (rubor)
- Heat (calor)
- Swelling (tumor)
- Pain (Dolor)
- Redness (rubor)
- Loss of function
What causes Redness (rubor)?
The dilation of small blood vessels within the damaged tissue
What causes heat (calor)?
Increased blood flow (hyperaemia) through the tissue, resulting in vascular dilation
What causes swelling (tumor)?
The accumulation of fluid in the extravascular space as part of the fluid exudate (due to high hydrostatic pressure). And to a lesser extent from the physical mass of inflammatory cells migrating to the area.
What causes Pain (dolor)?
The stretching and distortion of tissues due to inflammatory oedema and from pressurised puss in an abscess cavity.
What causes loss of function?
Movement in an inflamed area is consciously and reflexly inhibited by pain, while severe swelling can physically immobilise tissue.
What are the early stages of acute inflammation?
Oedema fluid, fibrin and neutrophil polymorphism accumulate in the extracellular spaces of the damaged tissue.
What is essential for a histological diagnosis of acute inflammation?
The presence of neutrophil polymorphs.
Acute inflammatory response process:
1) The vessel gets bigger (change in vessel calibre) - consequently vessel flow increases
2) Increased vascular permeability
3) Formation of the cellular exudate
What are the vascular changes observed in acute inflammation?
- The smooth muscle of arteriolar walls form precapillary sphincters which regulate blood flow through the capillaries (capillaries have no smooth muscle in their walls to control their calibre)
- Acute inflammation causes these sphincters to relax thus increasing blood flow through the capillaries contributing to redness and heat.
How does acute inflammation affect fluid return to the vascular compartment?
- Capillary hydrostatic pressure is increased as the precapillary sphincters relax
- This causes the escape of plasma proteins into the extravascular space, increasing osmotic pressure outside the vessel
- Vascular permeability increases causing swelling
Describe the movement of fluid in and out of a vessel under normal conditions.
High osmotic pressure inside the vessel, due to plasma proteins, favours fluid return into the vessel.
- High hydrostatic pressure at the arteriolar end forces fluid out into the extravascular space
- Lower hydrostatic pressure at the venous end allows for the return of fluid into the vascular compartment
What is Exudation?
The net escape of protein-rich fluid from the capillaries into the extravascular space.
- fluid is known as the fluid exudate.
What are the causes of increased vascular permeability and what is an example of each?
- Immediate transient causes - chemical mediators such as histamine (these are immediate but not permanent)
- Immediate sustained causes - Vascular injury - trauma
- Delayed prolonged causes - Endothelial cell injury - X-rays & bacterial toxins
What are the stages of neutrophil polymorph emigration?
1) Margination of neutrophils
2) Adhesion of neutrophils
3) Neutrophil emigration
Describe the margination of neutrophils.
- In normal circulation cells travel in the axial stream(centre of the vessel).
- Inflammation causes loss of intravascular fluid and increased plasma viscosity which causes neutrophils to travel in the plasmatic zone (peripheral - near the vessel walls/ endothelium)
Describe the adhesion of neutrophils.
- Neutrophils randomly come into contact with the endothelium in normal tissues but do not adhere
- Adhesion occurs due to the interaction of paired adhesion molecules on leucocyte and endothelial surfaces
- this only occurs in venules
The adhesion of neutrophils to the vascular endothelium is known as pavementing
Describe neutrophil emigration.
- White blood cells migrate through the walls of venules and small veins but do not commonly exit from capillaries
- Neutrophils insert pseudopodia between endothelial cells (which creates a small gap), they then migrate through the gap and then carry on through the basal lamina and into the vessel wall.
Describe Diapedesis.
- Red blood cells escape from the vessels passively due to the high hydrostatic pressure in the vessels forcing cells out.
- However the presence of a large number of RBC in the extracellular fluid implies vascular injury, such as a tear in a vessel wall
What is up-regulation?
An increase in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another agent.
What stimulates up-regulation?
Histamine and thrombin released by the original inflammatory stimulus (occurs early in the response).
What is the overall effect of chemical mediators in acute inflammation?
Firm neutrophil adhesion to the endothelial surface
What do endogenous chemical mediators cause?
- Vasodilation
- Emigration of neutrophils
- Chemotaxis (attraction of neutrophil polymorphs)
- Increased vascular permeability
- Itching and pain
What does Histamine cause to happen?
- vascular dilation
- And the immediate transient phase of increased vascular permeability.
What is the most important source of histamine?
Mast cells
Why is the effect of histamine immediate?
It is storied in preformed granules and so is able to be instantly released in tissues
What stimulates the release of histamine?
compliment components:
- C3a
- C5a
- And lysosomal proteins released from neutrophils.
What are 5 chemical mediators released from the cell in acute inflammation?
- Histamine
- Lysosomal compounds
- Eicosanoids (a type of prostaglandin)
- Serotonin
- Chemokines
What are the four enzymatic cascade systems present in the plasma?
1) the complement system
2) the kinins system
3) coagulation factors
4) fibrinolytic system
What is the compliment system and what is its purpose?
It’s a series of interacting plasma proteins which form a major effector system for antibody-mediated immune reactions. The major purpose of the compliment system is to remove or destroy antigens by direct lysis or opsonisation
Define opsonisation
The process by which bacteria are altered by opsonisation to become more readily and efficiently engulfed by phagocytosis
What are the chemical mediators of vascular dilatation
- Histamine
- Prostaglandins
- PGE2/12
- VIP
- Nitric oxide
- PAF
What are the chemical mediators of increased vascular permeability?
Transient phase - Histamine
Prolonged phase - Bradykinin, nitric oxide, C5a, Leucotriene B4 and PAF
What are the chemical mediators involved in adhesion of leucocytes to the endothelium?
- IL-8
- C5a
- Leucotriene
- B4
- PAF
- IL-1
- TNF-Alpha
What are the chemical mediators of neutrophil polymorph chemotaxis?
- Leucotriene B4
- IL-8
What is the role of tissue macrophages in acute inflammation?
The are responsible for clearing away tissue debris and damaged cells
What chemical mediators do tissue macrophages secrete when stimulated by local injury or infection?
- Interleukin-1
- TNF-alpha (tumour necrosis factor alpha)
When do macrophages become involved in acute inflammation?
Within a few hours, however they do not predominate until the later stages of infection when the neutrophil population has diminished.
Why is lymph drainage important in the immune response?
Antigens are carried to regional lymph nodes for recognition by lymphocytes which then produce antibodies.
What is the most common white blood cell?
Neutrophil polymorph - 60-70%
What colours does a neutrophil polymorph stain under H&E?
Nucleus stains blue, the cytoplasm stains pink/purple
What opsonises microorganisms?
Immunoglobulins or compliment proteins
What is the alternative pathway?
Bacterial toxins (liopopolysaccharides) activate the compliment system generating component C3b which has opsonising properties
What is the classical pathway?
When antibodies bind to bacterial antigens activating the compliment system generating C3b - which has opsonising properties
How do neutrophils bind to immunoglobulins (antibodies)?
The microorganisms bind to the FAB components of the antibody (the arms) and the FC component is left available to be bound to by neutrophils.
Which cells commonly implement phagocytosis?
- Neutrophil polymorphs
- macrophages
What are the stages of phagocytosis?
1) adhesion of the particle to be phagocytosed to the cell surface - facilitated by opsonisation
2) the phagocyte ingests the particle by sending a pseudopodia around it which meets and fuses so the particle is bound by a cell membrane in a phagosome.
3) lysosomes then fuse with the phagosome to form a phagolysosome - where the intracellular killing takes place
What oxygen-dependent noxious microbial agents are used in the intracellular killing of microorganisms during phagocytosis
- Hydrogen peroxide
Reacts with myeloperoxidase in the presence of a halide such as Cl- to produce a potent microbial agent
What oxygen-independent noxious microbial agents are used in the intracellular killing of microorganisms during phagocytosis
- Lysozymes (muramidase)
- Lactoferrin
What are the effects of lysosomal products?
- Damages local tissue by proteolysis (elastase and collagenase)
- Activates coagulation factor XII (7)
- Attracts other leucocytes to the area
- Inc vascular permeability
- Induce systemic fever by acting on hypothalamus (pyrogens)
What is the role of mast cells in acute inflammation?
- Release preformed inflammatory mediators (eg histamine)
- Metabolise arachidonic acid into inflammatory mediators such as leukotrienes, prostaglandins and thromboxanes.
What is the macroscopic appearance of acute inflammation?
- Serous inflammation - fluid release
- Suppurative inflammation - pus
- Membranous inflammation
- Pseudomembranous inflammation - formation of a membrane of a mucosal surface
- Necrotising inflammation - dead/ dying tissue
What are the beneficial effects of the fluid exudate on acute inflammation?
- dilution of toxins - carried away in lymphatics
- entry of antibodies - inc vascular permeability
- transport of drugs to site of infection
- fibrin formation to impede the movement of microorganisms by trapping them
- delivery of nutrients and O2 - essential for neutrophils which have high metabolic activity
- Stimulation of immune response by antigens entering the lymphatic system
What are the harmful effects of the fluid exudate on acute inflammation?
- Digestion of normal tissues - particularly vascular damage in type 3 sensitivity reactions
- Swelling - children - acute epiglottitis can obstruct the airway or in cranial cavity - raised intracranial pressure can impede bloodflow to brain - ischaemic damage
- Inappropriate inflammatory response - type 1 HSR
What are the four main outcomes of acute inflammation?
1) resolution
2) suppuration
3) organisation
4) progression to chronic inflammation
What is resolution and what conditions favour this outcome?
The complete restoration of tissues to normal after an episode of acute inflammation
- minimal cell death and damage
- occurrence in an organ capable of regeneration such as the liver
- rapid destruction of causal agent
- rapid removal of fluid and debris by good local drainage
EG - acute lobar pneumonia
What is suppuration and what conditions favour this outcome?
The formation of pus, a mixture of neutrophils, bacteria, cellular debris and sometimes globules of lipid
- the causative stimulus must be fairly persistent - usually an infective agent - usually pyogenic bacteria (pus forming bacteria)
- pus surrounded by pyogenic membrane - start of healing
- collection of pus - an abscess - bacteria within the cavity are relatively inaccessible to antibodies and antibiotic drugs.
What is empyema?
When pus accumulates inside a hollow organ, part of the organ may become fused together by fibrin resulting in an empyeme (pus filled pocket)
What is organisation and what conditions favour this outcome?
Organisation is the replacement of tissue by granulation tissue.
- large amounts of fibrin formed that cannot be removed completely by fibrinolytic enzymes from the plasma or neutrophil polymorphs
- substantial volumes of tissue become necrotic or the dead tissue is not easily digested
- exudate and debris cannot be removed or discharged
Eg - scaring in acute lobar pneumonia
What is the progression to chronic inflammation and what conditions favour this outcome?
The progression to a slow, long term inflammation which can last for months or years
- agent causing inflammation isn’t removed
- chronic inflammation often occurs as a primary event with there being no preceding period of acute inflammation
How does the nature of the fluid exudate change in chronic inflammation?
Instead of neutrophil polymorph:
- lymphocytes
- plasma cells (make antibodies)
- macrophages (phagocytose)
- multinucleate giant cells (comprising many macrophages that have combined all trying to engulf the same thing)
- fibroblasts (lay down collagen)
What are the systematic effects of inflammation?
- Pyrexia (fever)
- malaise (general feeling of unwellness)
- Anorexia (loss of appetite)
- Nausea
- Weight loss - due to -VE nitrogen balance because of the energy required to produce inflammatory mediators
- reactive hyperplasia
- haematological changes
- amyloidosis
What are examples of reactive hyperplasia of the reticuloendothelial system (clear up system)
- local or systematic lymph node enlargement
- Splenomegaly (spleen enlargement) - found in certain infections such as malaria and infectious mononucleosis
What are examples of haematological changes due to acute inflammation?
- increased levels of white blood cells
- inc in neutrophils - in pyogenic infections and tissue destruction
- inc in eosinophils - in allergic disorders and parasitic infections
- inc lymphocytes in chronic infection (eg tuberculosis), many viral infections and whooping cough
- increased amount of monocytes - in certain bacterial infections (eg tuberculosis and typhoid)
- anaemia - blood loss into exudate or due to haemolysis
What is amyloidosis and what cases it?
A build up of protein (amyloid plaque) - disrupting organ function
- long-standing chronic inflammation (eg TB)
- abnormal widening of the airways - inc mucus production
- elevation of serum amyloid A protein (SAA) can cause amyloid to be deposited in various tissues, resulting in secondary (reactive) amyloidosis.
(Secondary if it occurs due to another disease/ condition).
