Week 2 - Acute Inflammation Flashcards
1
Q
What is inflammation?
A
A response to injury of vascularised living tissue
2
Q
What is the purpose of inflammation?
A
- To deliver defensive materials (blood cells and fluid) to a site of injury
- To protect the body against infection (particularly bacterial)
- To clear damaged tissue
- To initiate tissue repair
3
Q
What are some characteristics of acute inflammation?
A
- Evolves over hours/days
- Innate
- Stereotyped
- Immediate
- Short duration
4
Q
What is acute inflammation?
A
A rapid response to an injurious agent that aims to deliver mediators of host defence (leukocytes and plasma proteins) to the site of injury
5
Q
What are some causes of acute inflammation?
A
- Foreign bodies
- Immune reactions
- Infections (bacterial, viral, parasitic) and microbial toxins
- Tissue necrosis
- Trauma (blunt and penetrating)
- Physical and chemical agents (thermal injury, irradiation, environmental chemicals)
6
Q
What are some characteristic signs of acute inflammation?
A
- Rubor = redness
- Tumor = swelling
- Color = heat
- Dolor = pain
Hence loss of function
7
Q
What are the changes in blood flow during acute inflammation?
A
- Transient vasoconstriction of arterioles (few seconds)
- Vasodilation of arteries and then capillaries, which leads to an increase in perfusion of the tissue (causing heat and redness)
- Increased permeability of blood vessels
8
Q
What is the effect of increased permeability of blood vessels in acute inflammation?
A
- Exudation of protein-rich fluid into tissues
- The fluid and leukocytes take up space within the tissues and so the inflamed area swells (oedema)
- Slowing of circulation due to swelling
- Gaps in the endothelial cells form, which the plasma fluid leaks through
- Arteriolar dilation leads to an increase in hydrostatic pressure, so there is greater exudation of vessels
9
Q
What are the main events in acute inflammation?
A
- Changes in blood flow
- Infiltration of inflammatory cells
- – Local defences are not adequate to protect against infection
- – Most defensive agents circulate in the blood in inactive form and are delivered and activated when needed
10
Q
Why are the changes seen with acute inflammation an effective response to injury?
A
- Delivers nutrients, oxygen, cells and plasma proteins (such as antibodies, inflammatory mediators, fibrinogen)
- Dilution of toxins
- Maintenance of temperature (some proteins can work faster and more effectively than at a higher temperature)
- Stimulation of immune response
- Destruction and removal of dead/foreign material
- Pain/loss of function enforcing rest, so that no further damage can occur
11
Q
What are neutrophil leucocytes?
A
They are the primary white blood cell involved in inflammation
- A type of granulatocyte
- Also known as a polymorphonuclear leucocyte
(Neutrophil = polymorph)
- Normally only found in the blood and bone marrow
- Their presence in the tissue indicates invasion by bacteria/some other parasite and/or tissue injury
- Have a lifespan of 12-20 hours
- An end cell
- Escape from blood vessels into tissue spaces in response to chemical ‘calls’ originating from bacteria, injured cells or other inflammatory cells
12
Q
How is a bacterium captured and killed in a tissue?
A
- Be summoned to the place of injury = chemotaxis
- Switch to a higher metabolic level = activation
- Stick to the endothelial surface = margination
- Crawl through the endothelium = diapedesis
- Recognise the bacterium and attach to it = recognition-attachment
- Engulf the bacterium = phagocytosis
13
Q
Describe chemotaxis
A
- The directional movement towards a chemical attractant (chemotaxin)
- Neutrophils move up a chemotactic gradient at approximately 30um/min (2mm/hour)
14
Q
What are some chemotaxins?
A
- Bacterial products
- Injured tissue
- Substances produced by leucocytes
- Spilled blood
- C5a complement fragment
- Clotted blood is chemotactic due to the thrombin and fibrin degradation
15
Q
Describe activation
A
- Within 5 seconds of the chemotaxis binding to the cell surface receptors, calcium and sodium ions rush into the cell
- This causes it to swell
- It reorganises its cytoskeleton
- The cell sends out pseudopodia
- Activated cells are stickier than normal cells
16
Q
What are the different types of endogenous mediators in inflammation?
A
- Vasoactive amines (e.g. histamine and serotonin)
- Vasoactive peptides (e.g. bradykinin)
- Complement components (e.g. C3a, C5a)
- Clotting and fibrinolytic cascades (both process generate inflammatory mediators)
- Mediators derived from phospholipids (e.g. prostaglandins, thrombaxanes and leukotrienes)
- Cytokines and chemokines (e.g. interleukins, tumour necrosis factor, interferons)
17
Q
What is bradykinin?
A
A vasoactive peptide that has similar effects to those of histamine
- It is produced very quickly
- It circulates in the blood as part of the larger molecule kinogen
- It is cleaved by kallikrein to produce bradykinin
18
Q
What is the function of complement proteins?
A
To form a tube which punches holes in bacteria, causing them to die
- They circulate in the blood as a number of disassembled proteins
- When it assembles into its tube structure it generates, as by-products) some powerful inflammatory mediators (C3a, C5a) and also the opsonin C3b
19
Q
What are cytokines?
A
Polypeptides that are produced by many cells and act as messengers between cells
- Many are produced by macrophages
20
Q
What are chemokines?
A
A group of cytokines that are involved in chemotaxis
- Have both local and systemic effects
- Start to appear in the hours following injury
21
Q
What is an example of an exogenous mediator in inflammation?
A
Endotoxin
- When it is released into tissue it causes inflammation
- If it is released into blood, it activates numerous inflammatory mechanisms at once, resulting in septic shick
22
Q
What are the main roles of inflammatory mediators?
A
- Vasodilation = histamine and serotonin (from mast cells and platelets), prostaglandins (from many cells)
- Increased vascular permeability = histamine, serotonin, bradykinin
- Chemotaxis = leukotriene B4, C5a and C3a, chemokines, bacterial products
- Phagocytosis = C3b
- Pain = bradykinin, prostaglandins
23
Q
What are the main sources of inflammatory mediators?
A
- Histamine and serotonin = from mast cells and platelets
- Prostaglandins = from many cells (from cell membrane phospholipids)
- Bradykinin = from kininogen
- Leukotriene B4 = from leucocytes
- Bacterial products = from bacterial metabolism
24
Q
What is histamine and what does it do?
A
A vasoactive mediator
- Causes vasodilation of arterioles
- Used in the brain as a neurotransmitter
- In acute inflammation it causes pain, arteriolar dilatation and venular leakage (histamine pulls endothelial cells apart, creating gaps through which plasma proteins can pass)
25
When is histamine released?
In response to many stimuli
| - E.g. physical damage, immune reactions, complement components
26
Where is histamine stored?
In the granules of mast cells, basophils and platelets
- Available immediately from preformed supplies
- Already present within cells in the tissues and platelets
27
What does serotonin do?
- It has similar vascular effects to histamine
- It stimulates fibroblasts
- Found in platelet granules
28
What do prostaglandins do?
- Cause vasodilation
- Make the skinnier sensitive to pain
- Cause fever
29
How and why are prostaglandins blocked?
By drugs such as aspirin and NSAIDS
| - This reduces pain and swelling
30
What does bradykinin do?
Produces pain and vascular permeability
31
What are the local complications of acute inflammation?
- Damage to normal tissue (secondary to substances produced by neutrophils and released during phagocytosis)
- Obstruction of tubes (secondary to swelling produced by the inflammatory exudate)
- Loss of fluid (in tissue spaces as fluid accumulates the tissue pressure increases until it reaches a level that prevents further exudation)
- Pain and loss of function
32
What are the systemic complications of acute inflammation?
- Fever
- Leucocytosis
- The acute phase response
- Shock
33
How can fever occur in acute inflammation?
- Occurs when the thermostat of the body is switched to a higher setting
- Macrophages produce pyrogenic cytokines when stimulated to do so
- These cytokines cause an increase in synthesis of prostaglandin E2 within the anterior hypothalamus
- It can be useful as some bacteria can't survive at higher temperatures
- Inflammation is more effective at higher temperatures
34
What is leucocytosis?
An increase in the number of circulating leucocytes
35
What is the acute phase response?
A change in the levels of some plasma proteins
- Due to the liver changing its pattern of protein synthesis
- Some proteins are produced in smaller amounts by the liver, some in larger amounts
- Occurs within hours of injury
- It is produced by cytokines released during inflammation
- The sleepiness and lack of appetite that are seen in serious injury are a result of this
36
What is shock?
A dramatic drop in blood pressure due to widespread vasodilation and increase in vascular permeability with resultant fluid exudation
- Often fatal
37
How does shock occur in acute inflammation?
Bacterial products/inflammatory mediators can spread throughout the body in the bloodstream
- This causes inflammation throughout the body
- This results in shock
38
What is an inflammatory mediator?
Any molecule that is produced in a focus of inflammation and modulates the inflammatory response in some way
- Every mediator has inhibitors
- They have short lives
- Their effects last minutes to hours
- Endogenous mediators are supplied by the plasma, leucocytes and local tissues
- Degraded after release
- Produced in quick bursts
- Present only as long as the stimulus persists
39
What happens in margination, rolling and adhesion?
- Margination
- The leucocytes roll along the endothelial wall, sticking to it intermittently
- They then stick more avidly
- Their receptors bind to adhesion molecules on the endothelium: selectins when rolling, integrins when they adhere and stick firmly
- The number of selectins and the activation of integrins is increased by inflammatory mediators and chemotaxins
- Adhesion activates the neutrophils to move and the endothelial cells to move further apart
40
What is margination?
The process whereby leucocytes assume marginal positions in the vessels
- They stick to the walls of venules
41
What happens during diapedesis?
- Leucocytes 'dig' their way out of the venues
- Produce collagenase, which digests the basement membrane
- Once in the extravascular space, the leucocytes more towards their target by pulling themselves along collagen fibres of other tissue structures
42
What are opsonins?
Substances which make it easier for phagocytes to recognise targets, attach to them, and then phagocytose them
43
What happens if opsonins are not present for phagocytosis?
The phagocyte recognises microbial surface antigens
44
What happens during phagocytosis?
- The membrane of the phagocyte forms a crater shape around the particle that is to be phagocytosed
- This crater then develops into a cup which surrounds the particle
- The edges of the cup come together and the apposed plasma membranes fuse together
- The particle is then within an intracellular vacuole which is called a phagosome
- The phagosome then proceeds to digest the particle
- The cell's granules move towards the phagosome, fuse with it and inject their bactericidal substances into it (degranulation)
45
What are the 2 mechanisms for killing cells during acute inflammation?
- Oxygen dependent: uses oxygen-derived free radicals (H2O2, O2-, OH-) which are released into the phagosome (an oxidative burst)
- Oxygen independent: uses enzymes
46
When does degranulation begin to occur?
Before the particle is completely enclosed by the phagocyte
- This allows some of the bactericidal enzymes to leak out into the surrounding tissue spaces
- May be harmful
47
What happens when the triggers for inflammation are removed?
- Normal vascular permeability returns
- Cessation of emigration of neutrophils
- Resolution of acute inflammation begins
- Exudate is reabsorbed into the venules/drained away in the lymphatics
- Fibrin is degraded (was present to localise the injury)
- Neutrophils undergo apoptosis and are phagocytosed along with necrotic debris by macrophages
- If the damaged parenchymal cells can regenerate then the tissue will return to normal, but if not then a fibrous scar will form
48
What are the consequences of acute inflammation?
- Complete resolution
- Can cause an abcess (fluid becomes trapped in a place from which it cannot be drained)
- Can cause scarring
- Death
49
Describe lobar pneumonia
- Due to an airborne infection with bacteria, viruses or myoplasma
- It is an acute exudative inflammation of an entire pulmonary lobe
- Mainly produced by streptococcus pneumonia
- If not treated, it evolves in 4 stages
- Common to all stages in the enlargement of the affected lobe with loss of its spongy appearance
- Only affects 1 lobe of the lung
- There is inflammation in the alveolar wall
- The air spaces are filled with fluid and pus, which contains bacteria and blood cells
50
Describe acute appendicits
- Usually caused by a bacterial infection, although the reason the appendix becomes infected is unknown
- The appendix may become obstructed by a lump of faeces, calcium salts and faecal debris, or tumours, leading to inflammation and infection
- Swelling and inflammation lead to infection, blood clot or rupture of the appendix
- If it is not treated promptly, there is a chance that the inflamed appendix will burst, spilling faecal material into the abdominal cavity
- This usually results in a potentially life-threatening infection but the infection may become sealed off and form an abcess
51
Describe bacterial meningitis
- May be caused by neisseria meningitidis or streptococcus pneumonia
- It is an infection of the protective membranes that surround the brain and spinal cord (the meninges)
- It causes them to become inflamed, which can damage the nerve and brain
52
Describe ascending cholangitis
- A bacterial infection
- An acute inflammatory disease of the bile duct
- An obstruction of the bile duct
- Commonly due to a gallstone
- May present with abdominal pain, jaundice and fever
- The flow of bile is reduced, so infection can occur
- Can cause vascular thrombosis and reduce cerebral perfusion
53
What is hereditary angio-oedema?
- An autosomal dominant disorder
- Extremely rare
- Sufferers have an inherited deficiency of C1-esterase inhibitor (part of the complement system)
- Patients have attacks of non-itchy cutaneous angio-oedema
- Also experience recurrent abdominal pain due to intestinal oedema
- Often a family history of sudden death due to laryngeal involvement
54
What is alpha-1-antitrypsin deficiency?
- An autosomal recessive disorder
- There are varying levels of severity
- There are low levels of alpha-1-antitrypsin, a protease inhibitor which deactivates enzymes released from neutrophils at the site of inflammation
- Emphysema develops since proteases released by neutrophils act unchecked within the lung, and destroy normal parenchymal tissue
- Liver disease also occurs as the hepatocytes produce an abnormal version of the protein which is incorrectly folded
- This protein polymerises and causes hepatocyte damage (since can't be exported from the ER) which eventually results in cirrhosis
55
What is chronic granulomatous disease?
- Phagocytes are unable to generate superoxide
- Bacteria are phagocytose but the phagocytes cannot kill them since they can't generate an oxidative burst
- This results in th formation of chronic infections in the 1st year of life
- Numerous granulomas and abcesses affecting the skin, lymph nodes and sometimes the lung, liver and bones occur since the body is ineffective at eliminating infectious agents
56
What is exudate?
Fluid loss in inflammation, with a high protein content
57
What is transudate?
Fluid loss due to hydrostatic pressure imbalance, with a low protein content
58
What different types of exudate are there?
Pus/abcess:
- Creamy/white exudate as it is rich in neutrophils
- Typical of infections by chemotactic bacteria
Haemorrhagic
- Contains enough red blood cells to appear bloody to the naked eye
- Indicates that there is significant vascular damage as well as inflammation
- Seen in destructive infections or when the exudate is a result of infiltration by a malignant tumour
Serous
- Contains plasma proteins but few leucocytes
- Suggests there is no infection by microorganisms
- Clear
- Typically seen in blisters
Fibrous
- Significant deposition of fibrin
- If they occur in the pericardial or pleural spaces then fibrin is deposited, so the serosal surfaces no longer slide over each other smoothly
- This causes friction and a rubbing sound
